Margaret McEntegart

Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program.

Background— We wished to determine the prevalence of, potential mechanistic associations of, and clinical outcomes related to anemia in patients with heart failure and a broad spectrum of left ventricular ejection fraction (LVEF). Methods and Results— In multivariable analyses, we examined the associations between hemoglobin and baseline characteristics, laboratory variables, and outcomes in 2653 patients randomized in the CHARM Program in the United States and Canada. Anemia was equally common in patients with preserved (27%) and reduced (25%) LVEF but was more common in black and older patients. Anemia was associated with ethnicity, diabetes, low body mass index, higher systolic and lower diastolic blood pressure, and recent heart failure hospitalization. More than 50% of anemic patients had a glomerular filtration rate <60 mL · min−1 · 1.73 m−2 compared with <30% of nonanemic patients. Despite an inverse relationship between hemoglobin and LVEF, anemia was associated with an increased risk of death and hospitalization, a relationship observed in patients with both reduced and preserved LVEF. There were 133 versus 69 deaths and 527 versus 352 hospitalizations per 1000 patient-years of follow-up in anemic versus nonanemic patients (both P<0.001). The effect of candesartan in reducing outcomes was independent of hemoglobin. Conclusions— Anemia was common in heart failure, regardless of LVEF. Lower hemoglobin was associated with higher LVEF yet was an independent predictor of adverse mortality and morbidity outcomes. In heart failure, the causes of anemia and the associations between anemia and outcomes are probably multiple and complex.

Sex Differences in Clinical Characteristics and Prognosis in a Broad Spectrum of Patients With Heart Failure Results of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Program

Background— We wished to test previous hypotheses that sex-related differences in mortality and morbidity may be due to differences in the cause of heart failure or in left ventricular ejection fraction (LVEF) by comparing fatal and nonfatal outcomes in women and men with heart failure and a broad spectrum of left ventricular ejection fraction. Methods and Results— We compared outcomes in 2400 women and 5199 men randomized in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program using multivariable regression analyses. A total of 1188 women (50%) had a low LVEF (≤0.40), and 1212 had a preserved LVEF (>0.40). Among the men, 3388 (65%) had a low LVEF, and 1811 had a preserved LVEF. A total of 1216 women (51%) and 3465 men (67%) had an ischemic cause of their heart failure. All-cause mortality was 21.5% in women and 25.3% in men (adjusted hazard ratio [HR], 0.77; 95% CI, 0.69 to 0.86; P<0.001). Fewer women (30.4%) than men (33.3%) experienced cardiovascular death or heart failure hospitalization (adjusted HR, 0.83; 95% CI, 0.76 to 0.91; P<0.001). The risks of sudden death (HR, 0.70; 95% CI, 0.58 to 0.85) and death due to worsening heart failure (HR, 0.72; 95% CI, 0.58 to 0.89) were reduced to a comparable extent. The adjusted risk of cardiovascular hospitalization was also lower in women (HR, 0.88; 95% CI, 0.82 to 0.95), mainly because of a reduced risk of heart failure hospitalization (HR, 0.87; 95% CI, 0.78 to 0.97). Women had a lower risk of death irrespective of cause of heart failure or LVEF. Conclusions— Among patients with heart failure, women have lower risks of most fatal and nonfatal outcomes that are not explained, as previously suggested, by LVEF or origin of the heart failure.

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)

Microvascular Resistance Predicts Myocardial Salvage and Infarct Characteristics in ST-Elevation Myocardial Infarction

Background The pathophysiology of myocardial injury and repair in patients with ST‐elevation myocardial infarction is incompletely understood. We investigated the relationships among culprit artery microvascular resistance, myocardial salvage, and ventricular function. Methods and Results The index of microvascular resistance (IMR) was measured by means of a pressure‐ and temperature‐sensitive coronary guidewire in 108 patients with ST‐elevation myocardial infarction (83% male) at the end of primary percutaneous coronary intervention. Paired cardiac MRI (cardiac magnetic resonance) scans were performed early (2 days; n=108) and late (3 months; n=96) after myocardial infarction. T2‐weighted‐ and late gadolinium–enhanced cardiac magnetic resonance delineated the ischemic area at risk and infarct size, respectively. Myocardial salvage was calculated by subtracting infarct size from area at risk. Univariable and multivariable models were constructed to determine the impact of IMR on cardiac magnetic resonance–derived surrogate outcomes. The median (interquartile range) IMR was 28 (17–42) mm Hg/s. The median (interquartile range) area at risk was 32% (24%–41%) of left ventricular mass, and the myocardial salvage index was 21% (11%–43%). IMR was a significant multivariable predictor of early myocardial salvage, with a multiplicative effect of 0.87 (95% confidence interval 0.82 to 0.92) per 20% increase in IMR; P<0.001. In patients with anterior myocardial infarction, IMR was a multivariable predictor of early and late myocardial salvage, with multiplicative effects of 0.82 (95% confidence interval 0.75 to 0.90; P<0.001) and 0.92 (95% confidence interval 0.88 to 0.96; P<0.001), respectively. IMR also predicted the presence and extent of microvascular obstruction and myocardial hemorrhage. Conclusion Microvascular resistance measured during primary percutaneous coronary intervention significantly predicts myocardial salvage, infarct characteristics, and left ventricular ejection fraction in patients with ST‐elevation myocardial infarction. (J Am Heart Assoc. 2012;1:e002246 doi: 10.1161/JAHA.112.002246)

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)

Diaphragm Ultrasonography as an Alternative to Whole-Body Plethysmography in Pulmonary Function Testing

Objective. Whole‐body plethysmography is a common method of measuring pulmonary function. Although this technique provides a sensitive measure of pulmonary function, it can be problematic and unsuitable in some patients. The development of more accessible techniques would be beneficial. Methods. A prospective study was performed to validate diaphragm ultrasonography as an alternative to whole‐body plethysmography in patients referred for pulmonary function testing. Diaphragm movement and position were assessed by ultrasonography after standard pulmonary function testing using whole‐body plethysmography. Results. A wide range of lung function was observed. Standard lung volumes were as follows: total lung capacity, 5.57 ± 1.31 L, residual volume, 2.27 ± 0.56 L; and vital capacity, 3.30 ± 0.98 L (mean ± SD). The ratio of forced expiratory volume in 1 second to forced vital capacity was calculated as 0.69 ± 0.08. Ultrasonography showed that mean diaphragm excursion values were 11.1 ± 3.8 mm (2‐dimensional), 14.7 ± 4.1 mm during quiet breathing (M‐mode), and 14.8 ± 3.9 mm during a maximal sniff (M‐mode). The velocity of diaphragm movement rose sharply during the sniff maneuver from 15.2 ± 5.8 mm/s during quiet breathing to 104.0 ± 33.4 mm/s. Static 2‐dimensional measures of diaphragm position at the end of quiet inspiration or expiration correlated with standard measures of lung volume on plethysmography (eg, a correlation coefficient of 0.83 was obtained with end inspiration and vital capacity). All measures of diaphragm movement (whether by 2‐dimensional or M‐mode techniques) were poorly correlated with any lung volumes measured. Conclusions. These data suggest that dynamic measurements using diaphragm ultrasonography provide a relatively poor measure of pulmonary function in relation to whole‐body plethysmography.

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.

Vasodilatory Capacity of the Coronary Microcirculation is Preserved in Selected Patients With Non–ST-Segment–Elevation Myocardial Infarction

Background—The use of fractional flow reserve in patients with non–ST-segment–elevation myocardial infarction (NSTEMI) is a controversial issue. We undertook a study to assess the vasodilatory capacity of the coronary microcirculation in patients with NSTEMI when compared with a model of preserved microcirculation (stable angina [SA] cohort: culprit and nonculprit vessel) and acute microcirculatory dysfunction (ST-segment–elevation myocardial infarction [STEMI] cohort). We hypothesized that the vasodilatory response of the microcirculation would be preserved in NSTEMI. Methods and Results—A total of 140 patients undergoing single vessel percutaneous coronary intervention were included: 50 stable angina, 50 NSTEMI, and 40 STEMI. The index of microvascular resistance (IMR), fractional flow reserve, and coronary flow reserve were measured before stenting in the culprit vessel and in an angiographically normal nonculprit vessel in patients with SA. The resistive reserve ratio, a measure of the vasodilatory capacity of the microcirculation and calculated using the equation: baseline resistance index (TmnBase×PaBase[PdBase–Pw/PaBase–Pw])–IMR/IMR, where TmnBase referred to nonhyperemic transit time; PaBase and PdBase, the nonhyperemic aortic and distal coronary pressures, respectively; and Pw referred to the coronary wedge pressure, was also measured. Troponin was also measured ⩽24 hours after percutaneous coronary intervention. The resistive reserve ratio was significantly lower in the STEMI patients compared with the stable angina patients both culprit and nonculprit vessel (STEMI, 1.7 versus SA culprit, 2.8; P⩽0.001 and SA nonculprit, 2.9; P<0.0001) and compared with NSTEMI patients (NSTEMI, 2.46; P⩽0.001). The resistive reserve ratio was similar in stable angina and NSTEMI patients (P=0.6). IMR was significantly higher pre-PCI in STEMI compared with SA and NSTEMI (IMR STEMI, 36.51 versus IMR NSTEMI, 22.73 [P=0.01] versus IMR SA, 18.26 [P<0.0001]). However, there was no significant difference in IMR pre-PCI between NSTEMI and SA (IMR NSTEMI, 22.73; IMR SA, 18.26 [P=0.1]). Conclusions—The vasodilatory capacity of the microcirculation is preserved in selected patients with NSTEMI. The clinical use of fractional flow reserve in the culprit vessel may be preserved in selected patents with NSTEMI.

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.