Stuart Watkins

Validation of Magnetic Resonance Myocardial Perfusion Imaging With Fractional Flow Reserve for the Detection of Significant Coronary Heart Disease

Background— Magnetic resonance myocardial perfusion imaging (MRMPI) has a number of advantages over the other noninvasive tests used to detect reversible myocardial ischemia. The majority of previous studies have generally used quantitative coronary angiography as the gold standard to assess the accuracy of MRMPI; however, only an approximate relationship exists between stenosis severity and functional significance. Pressure wire–derived fractional flow reserve (FFR) values <0.75 correlate closely with objective evidence of reversible ischemia. Accordingly, we have compared MRMPI with FFR. Methods and Results— One hundred three patients referred for investigation of suspected angina underwent MRMPI with a 1.5-T scanner. The stress agent was intravenous adenosine (140 &mgr;g · kg−1 · min−1), and the first-pass bolus contained 0.1 mmol/kg gadolinium. In the following week, coronary angiography with pressure wire studies was performed. FFR was recorded in all patent major epicardial coronary arteries, with a value <0.75 denoting significant stenosis. MRMPI scans, analyzed by 2 blinded observers, identified perfusion defects in 121 of 300 coronary artery segments (40%), of which 110 had an FFR <0.75. We also found that 168 of 179 normally perfused segments had an FFR ≥0.75. The sensitivity and specificity of MRMPI for the detection of functionally significant coronary heart disease were 91% and 94%, respectively, with positive and negative predictive values of 91% and 94%. Conclusion— MRMPI can detect functionally significant coronary heart disease with excellent sensitivity, specificity, and positive and negative predictive values compared with FFR.

A randomized trial of deferred stenting versus immediate stenting to prevent no- or slow-reflow in acute ST-segment elevation myocardial infarction (DEFER-STEMI).

Objectives The aim of this study was to assess whether deferred stenting might reduce no-reflow and salvage myocardium in primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Background No-reflow is associated with adverse outcomes in STEMI. Methods This was a prospective, single-center, randomized, controlled, proof-of-concept trial in reperfused STEMI patients with ≥1 risk factors for no-reflow. Randomization was to deferred stenting with an intention-to-stent 4 to 16 h later or conventional treatment with immediate stenting. The primary outcome was the incidence of no-/slow-reflow (Thrombolysis In Myocardial Infarction ≤2). Cardiac magnetic resonance imaging was performed 2 days and 6 months after myocardial infarction. Myocardial salvage was the final infarct size indexed to the initial area at risk. Results Of 411 STEMI patients (March 11, 2012 to November 21, 2012), 101 patients (mean age, 60 years; 69% male) were randomized (52 to the deferred stenting group, 49 to the immediate stenting). The median (interquartile range [IQR]) time to the second procedure in the deferred stenting group was 9 h (IQR: 6 to 12 h). Fewer patients in the deferred stenting group had no-/slow-reflow (14 [29%] vs. 3 [6%]; p = 0.006), no reflow (7 [14%] vs. 1 [2%]; p = 0.052) and intraprocedural thrombotic events (16 [33%] vs. 5 [10%]; p = 0.010). Thrombolysis In Myocardial Infarction coronary flow grades at the end of PCI were higher in the deferred stenting group (p = 0.018). Recurrent STEMI occurred in 2 patients in the deferred stenting group before the second procedure. Myocardial salvage index at 6 months was greater in the deferred stenting group (68 [IQR: 54% to 82%] vs. 56 [IQR: 31% to 72%]; p = 0.031]. Conclusions In high-risk STEMI patients, deferred stenting in primary PCI reduced no-reflow and increased myocardial salvage. (Deferred Stent Trial in STEMI; NCT01717573)

The index of microcirculatory resistance measured acutely predicts the extent and severity of myocardial infarction in patients with ST-segment elevation myocardial infarction.

OBJECTIVES This study investigated the relationship between the index of microcirculatory resistance (IMR) with myocardial injury and microvascular obstruction (MVO) assessed by contrast-enhanced cardiac magnetic resonance (ceCMR) imaging in a broad range of ST-segment elevation myocardial infarction (STEMI) patients undergoing emergency percutaneous coronary intervention (PCI). BACKGROUND Contrast-enhanced cardiac magnetic resonance imaging is the gold standard for assessment of microvascular obstruction (MVO), left ventricular (LV) ejection fraction, and infarct volumes in ST-segment elevation myocardial infarction (STEMI). However, ceCMR is not available acutely. The index of microcirculatory resistance is a simple invasive measure of microvascular function available at the time of emergency PCI. We investigated the relationship between IMR with myocardial injury and MVO assessed by ceCMR in STEMI patients undergoing emergency PCI. METHODS Fifty-seven patients with STEMI were included and 53 (93%) and 47 (82%) patients had complete ceCMR scans 2 days and 3 months following MI, respectively. Microvascular obstruction was defined as a dark core of hypoenhancement within the area of hyperenhanced infarct tissue 10 to 15 min following intravenous gadolinium (0.1 mmol/kg). RESULTS The median IMR (interquartile range [IQR]) was 35 (24 to 63) U. Twenty-seven patients (46%) had MVO. We found that IMR (median [IQR]) was higher in patients with MVO (38 [29 to 55] U) than in patients without MVO (27 [18 to 36] U); p = 0.003). The index of microcirculatory resistance was a negative multivariable predictor of LV ejection fraction, (p < or = 0.001) and infarct volume (p = 0.01) on the ceCMR scan 2 days after MI, and IMR was a multivariable predictor of LV ejection fraction (p = 0.028) and infarct volume (p = 0.048) at 3 months. CONCLUSIONS The index of microcirculatory resistance measured acutely was higher in patients with MVO on ceCMR, and IMR independently predicted LV function and infarct volume. This easily measured physiological parameter provides important prognostic information at the time of emergency PCI.

Pathophysiology of LV Remodeling in Survivors of STEMI: Inflammation, Remote Myocardium, and Prognosis

Objectives The aim of this study was to investigate the clinical significance of native T1 values in remote myocardium in survivors of acute ST-segment elevation myocardial infarction (STEMI). Background The pathophysiology and prognostic significance of remote myocardium in the natural history of STEMI is uncertain. Cardiac magnetic resonance (CMR) reveals myocardial function and pathology. Native T1 (relaxation time in ms) is a fundamental magnetic resonance tissue property determined by water content and cellularity. Results A total of 300 STEMI patients (mean age 59 years; 74% male) gave informed consent. A total of 288 STEMI patients had evaluable native T1 CMR, and 267 patients (91%) had follow-up CMR at 6 months. Health outcome information was obtained for all of the participants (median follow-up 845 days). Infarct size was 18 ± 13% of left ventricular (LV) mass. Two days post-STEMI, native T1 was lower in remote myocardium than in the infarct zone (961 ± 25 ms vs. 1,097 ± 52 ms; p < 0.01). In multivariable regression, incomplete ST-segment resolution was associated with myocardial remote zone native T1 (regression coefficient 9.42; 95% confidence interval [CI]: 2.37 to 16.47; p = 0.009), as were the log of the admission C-reactive protein concentration (3.01; 95% CI: 0.016 to 5.85; p = 0.038) and the peak monocyte count (10.20; 95% CI: 0.74 to 19.67; p = 0.035). Remote T1 at baseline was associated with log N-terminal pro–B-type natriuretic peptide at 6 months (0.01; 95% CI: 0.00 to 0.02; p = 0.002; n = 151) and the change in LV end-diastolic volume from baseline to 6 months (0.13; 95% CI: 0.01 to 0.24; p = 0.035). Remote zone native T1 was independently associated with post-discharge major adverse cardiac events (n = 20 events; hazard ratio: 1.016; 95% CI: 1.000 to 1.032; p = 0.048) and all-cause death or heart failure hospitalization (n = 30 events during admission and post-discharge; hazard ratio: 1.014; 95% CI: 1.000 to 1.028; p = 0.049). Conclusions Reperfusion injury and inflammation early post-MI was associated with remote zone T1, which in turn was independently associated with LV remodeling and adverse cardiac events post-STEMI. (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850)

Temporal Evolution of Myocardial Hemorrhage and Edema in Patients After Acute ST‐Segment Elevation Myocardial Infarction: Pathophysiological Insights and Clinical Implications

Background The time course and relationships of myocardial hemorrhage and edema in patients after acute ST‐segment elevation myocardial infarction (STEMI) are uncertain. Methods and Results Patients with ST‐segment elevation myocardial infarction treated by primary percutaneous coronary intervention underwent cardiac magnetic resonance imaging on 4 occasions: at 4 to 12 hours, 3 days, 10 days, and 7 months after reperfusion. Myocardial edema (native T2) and hemorrhage (T2*) were measured in regions of interest in remote and injured myocardium. Myocardial hemorrhage was taken to represent a hypointense infarct core with a T2* value <20 ms. Thirty patients with ST‐segment elevation myocardial infarction (mean age 54 years; 25 [83%] male) gave informed consent. Myocardial hemorrhage occurred in 7 (23%), 13 (43%), 11 (33%), and 4 (13%) patients at 4 to 12 hours, 3 days, 10 days, and 7 months, respectively, consistent with a unimodal pattern. The corresponding median amounts of myocardial hemorrhage (percentage of left ventricular mass) during the first 10 days after myocardial infarction were 2.7% (interquartile range [IQR] 0.0–5.6%), 7.0% (IQR 4.9–7.5%), and 4.1% (IQR 2.6–5.5%; P<0.001). Similar unimodal temporal patterns were observed for myocardial edema (percentage of left ventricular mass) in all patients (P=0.001) and for infarct zone edema (T2, in ms: 62.1 [SD 2.9], 64.4 [SD 4.9], 65.9 [SD 5.3]; P<0.001) in patients without myocardial hemorrhage. Alternatively, in patients with myocardial hemorrhage, infarct zone edema was reduced at day 3 (T2, in ms: 51.8 [SD 4.6]; P<0.001), depicting a bimodal pattern. Left ventricular end‐diastolic volume increased from baseline to 7 months in patients with myocardial hemorrhage (P=0.001) but not in patients without hemorrhage (P=0.377). Conclusions The temporal evolutions of myocardial hemorrhage and edema are unimodal, whereas infarct zone edema (T2 value) has a bimodal pattern. Myocardial hemorrhage is prognostically important and represents a target for therapeutic interventions that are designed to preserve vascular integrity following coronary reperfusion. Clinical Trial Registration URL: https://clinicaltrials.gov/. Unique identifier: NCT02072850.

Prognostic significance of infarct core pathology revealed by quantitative non-contrast in comparison with contrast cardiac magnetic resonance imaging in reperfused ST-elevation myocardial infarction survivors

Abstract Aims To assess the prognostic significance of infarct core tissue characteristics using cardiac magnetic resonance (CMR) imaging in survivors of acute ST-elevation myocardial infarction (STEMI). Methods and results We performed an observational prospective single centre cohort study in 300 reperfused STEMI patients (mean ± SD age 59 ± 12 years, 74% male) who underwent CMR 2 days and 6 months post-myocardial infarction (n = 267). Native T1 was measured in myocardial regions of interest (n = 288). Adverse remodelling was defined as an increase in left ventricular (LV) end-diastolic volume ≥20% at 6 months. All-cause death or first heart failure hospitalization was a pre-specified outcome that was assessed during follow-up (median duration 845 days). One hundred and sixty (56%) patients had a hypo-intense infarct core disclosed by native T1. In multivariable regression, infarct core native T1 was inversely associated with adverse remodelling [odds ratio (95% confidence interval (CI)] per 10 ms reduction in native T1: 0.91 (0.82, 0.00); P = 0.061). Thirty (10.4%) of 288 patients died or experienced a heart failure event and 13 of these events occurred post-discharge. Native T1 values (ms) within the hypo-intense infarct core (n = 160 STEMI patients) were inversely associated with the risk of all-cause death or first hospitalization for heart failure post-discharge (for a 10 ms increase in native T1: hazard ratio 0.730, 95% CI 0.617, 0.863; P < 0.001) including after adjustment for left ventricular ejection fraction, infarct core T2 and myocardial haemorrhage. The prognostic results for microvascular obstruction were similar. Conclusion Infarct core native T1 represents a novel non-contrast CMR biomarker with potential for infarct characterization and prognostication in STEMI survivors. Confirmatory studies are warranted. ClinicalTrials.gov identifier NCT02072850.

Bright-blood T(2)-weighted MRI has high diagnostic accuracy for myocardial hemorrhage in myocardial infarction: a preclinical validation study in swine.

Background— Myocardial hemorrhage after myocardial infarction (MI) usually goes undetected. We investigated the diagnostic accuracy of bright-blood T2-weighted cardiac MRI for myocardial hemorrhage in experimental MI. Methods and Results— MI was created in swine by occluding the left anterior descending (n=10) or circumflex (n=5) coronary arteries for 90 minutes followed by reperfusion for ⩽3 days (n=2), 10 days (n=7), or 60 days (n=6). MRI was performed at 1.5 T, using bright-blood T2-prepared steady-state free-precession, T2* and early (1 minute) and late (10–15 minutes) gadolinium enhancement (EGE, LGE, respectively) MRI. Left ventricular sections and histology were assessed for hemorrhage by an experienced cardiac pathologist blinded to the MRI data. Hypointense regions on T2-weighted and contrast-enhanced MRI were independently determined by 3 cardiologists experienced in MRI who were also blinded to the pathology results. Eighty ventricular pathological sections were matched with MRI (n=68 for EGE MRI). All sections with evidence of MI (n=63, 79%) also exhibited hyperintense zones consistent with edema on T2-weighted MRI and infarct on LGE MRI. Myocardial hemorrhage occurred in 49 left ventricular sections (61%) and corresponded with signal voids on 48 T2-weighted (98%) and 26 LGE-MRI (53%). Alternatively, signal voids occurred in the absence of hemorrhage in 3 T2-weighted (90% specificity) and 5 LGE MRI (84% specificity). On EGE MRI, 27 of 43 cases of early microvascular obstruction corresponded with hemorrhage (63% sensitivity), whereas 5 of 25 defects occurred in the absence of hemorrhage (80% specificity). The positive and negative predictive values for pathological evidence of hemorrhage were 94% and 96% for T2-weighted, 84% and 55% for LGE MRI, and 85% and 56% for EGE MRI. Conclusions— Bright-blood T2-weighted MRI has high diagnostic accuracy for myocardial hemorrhage.

Myocardial Hemorrhage After Acute Reperfused ST-Segment–Elevation Myocardial Infarction: Relation to Microvascular Obstruction and Prognostic Significance

Background—The success of coronary reperfusion therapy in ST-segment–elevation myocardial infarction (MI) is commonly limited by failure to restore microvascular perfusion. Methods and Results—We performed a prospective cohort study in patients with reperfused ST-segment–elevation MI who underwent cardiac magnetic resonance 2 days (n=286) and 6 months (n=228) post MI. A serial imaging time-course study was also performed (n=30 participants; 4 cardiac magnetic resonance scans): 4 to 12 hours, 2 days, 10 days, and 7 months post reperfusion. Myocardial hemorrhage was taken to represent a hypointense infarct core with a T2* value of <20 ms. Microvascular obstruction was assessed with late gadolinium enhancement. Adverse remodeling was defined as an increase in left ventricular end-diastolic volume ≥20% at 6 months. Cardiovascular death or heart failure events post discharge were assessed during follow-up. Two hundred forty-five patients had evaluable T2* data (mean±age, 58 [11] years; 76% men). Myocardial hemorrhage 2 days post MI was associated with clinical characteristics indicative of MI severity and inflammation. Myocardial hemorrhage was a multivariable associate of adverse remodeling (odds ratio [95% confidence interval]: 2.64 [1.07–6.49]; P=0.035). Ten (4%) patients had a cardiovascular cause of death or experienced a heart failure event post discharge, and myocardial hemorrhage, but not microvascular obstruction, was associated with this composite adverse outcome (hazard ratio, 5.89; 95% confidence interval, 1.25–27.74; P=0.025), including after adjustment for baseline left ventricular end-diastolic volume. In the serial imaging time-course study, myocardial hemorrhage occurred in 7 (23%), 13 (43%), 11 (33%), and 4 (13%) patients 4 to 12 hours, 2 days, 10 days, and 7 months post reperfusion. The amount of hemorrhage (median [interquartile range], 7.0 [4.9–7.5]; % left ventricular mass) peaked on day 2 (P<0.001), whereas microvascular obstruction decreased with time post reperfusion. Conclusions—Myocardial hemorrhage and microvascular obstruction follow distinct time courses post ST-segment–elevation MI. Myocardial hemorrhage was more closely associated with adverse outcomes than microvascular obstruction. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850.

Integrated Physiologic Assessment of Ischemic Heart Disease in Real-World Practice Using Index of Microcirculatory Resistance and Fractional Flow Reserve Insights From the International Index of Microcirculatory Resistance Registry

Background—The index of microcirculatory resistance (IMR) is a quantitative and specific index for coronary microcirculation. However, the distribution and determinants of IMR have not been fully investigated in patients with ischemic heart disease (IHD). Methods and Results—Consecutive patients who underwent elective measurement of both fractional flow reserve (FFR) and IMR were enrolled from 8 centers in 5 countries. Patients with acute myocardial infarction were excluded. To adjust for the influence of collateral flow, IMR values were corrected with Yong’s formula (IMRcorr). High IMR was defined as greater than the 75th percentile in each of the major coronary arteries. FFR⩽0.80 was defined as an ischemic value. 1096 patients with 1452 coronary arteries were analyzed (mean age 61.1, male 71.2%). Mean FFR was 0.84 and median IMRcorr was 16.6 U (Q1, Q3 12.4 U, 23.0 U). There was no correlation between IMRcorr and FFR values (r=0.01, P=0.62), and the categorical agreement of FFR and IMRcorr was low (kappa value=−0.04, P=0.10). There was no correlation between IMRcorr and angiographic % diameter stenosis (r=−0.03, P=0.25). Determinants of high IMR were previous myocardial infarction (odds ratio [OR] 2.16, 95% confidence interval [CI] 1.24–3.74, P=0.01), right coronary artery (OR 2.09, 95% CI 1.54–2.84, P<0.01), female (OR 1.67, 95% CI 1.18–2.38, P<0.01), and obesity (OR 1.80, 95% CI 1.31–2.49, P<0.01). Determinants of FFR ⩽0.80 were left anterior descending coronary artery (OR 4.31, 95% CI 2.92–6.36, P<0.01), angiographic diameter stenosis ≥50% (OR 5.16, 95% CI 3.66–7.28, P<0.01), male (OR 2.15, 95% CI 1.38–3.35, P<0.01), and age (per 10 years, OR 1.21, 95% CI 1.01–1.46, P=0.04). Conclusions—IMR showed no correlation with FFR and angiographic lesion severity, and the predictors of high IMR value were different from those for ischemic FFR value. Therefore, integration of IMR into FFR measurement may provide additional insights regarding the relative contribution of macro- and microvascular disease in patients with ischemic heart disease. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02186093.

Comparative prognostic utility of indexes of microvascular function alone or in combination in patients with an acute ST-segment elevation myocardial infarction

Background: Primary percutaneous coronary intervention is frequently successful at restoring coronary artery blood flow in patients with acute ST-segment–elevation myocardial infarction; however, failed myocardial reperfusion commonly passes undetected in up to half of these patients. The index of microvascular resistance (IMR) is a novel invasive measure of coronary microvascular function. We aimed to investigate the pathological and prognostic significance of an IMR>40, alone or in combination with a coronary flow reserve (CFR⩽2.0), in the culprit artery after emergency percutaneous coronary intervention for acute ST-segment–elevation myocardial infarction. Methods: Patients with acute ST-segment–elevation myocardial infarction were prospectively enrolled during emergency percutaneous coronary intervention and categorized according to IMR (⩽40 or >40) and CFR (⩽2.0 or >2.0). Cardiac magnetic resonance imaging was acquired 2 days and 6 months after myocardial infarction. All-cause death or first heart failure hospitalization was a prespecified outcome (median follow-up, 845 days). Results: IMR and CFR were measured in the culprit artery at the end of percutaneous coronary intervention in 283 patients with ST-segment–elevation myocardial infarction (mean±SD age, 60±12 years; 73% male). The median IMR and CFR were 25 (interquartile range, 15–48) and 1.6 (interquartile range, 1.1–2.1), respectively. An IMR>40 was a multivariable associate of myocardial hemorrhage (odds ratio, 2.10; 95% confidence interval, 1.03–4.27; P=0.042). An IMR>40 was closely associated with microvascular obstruction. Symptom-to-reperfusion time, TIMI (Thrombolysis in Myocardial Infarction) blush grade, and no (⩽30%) ST-segment resolution were not associated with these pathologies. An IMR>40 was a multivariable associate of the changes in left ventricular ejection fraction (coefficient, −2.12; 95% confidence interval, −4.02 to −0.23; P=0.028) and left ventricular end-diastolic volume (coefficient, 7.85; 95% confidence interval, 0.41–15.29; P=0.039) at 6 months independently of infarct size. An IMR>40 (odds ratio, 4.36; 95% confidence interval, 2.10–9.06; P<0.001) was a multivariable associate of all-cause death or heart failure. Compared with an IMR>40, the combination of IMR>40 and CFR⩽2.0 did not have incremental prognostic value. Conclusions: An IMR>40 is a multivariable associate of left ventricular and clinical outcomes after ST-segment–elevation myocardial infarction independently of the infarction size. Compared with standard clinical measures of the efficacy of myocardial reperfusion, including the ischemic time, ST-segment elevation, angiographic blush grade, and CFR, IMR has superior clinical value for risk stratification and may be considered a reference test for failed myocardial reperfusion. Clinical Trial Registration: URL: https//www.clinicaltrials.gov. Unique identifier: NCT02072850.