Andrew T. Yan

BACKGROUND: Accurate risk stratification is crucial for effective treatment planning after myocardial infarction (MI). Previous studies suggest that the peri-infarct border zone may be an important arrhythmogenic substrate. In this pilot study, we tested the hypothesis that the extent of the peri-infarct zone quantified by contrast-enhanced cardiac magnetic resonance (CMR) is an independent predictor of post-MI mortality. METHODS AND RESULTS: We studied 144 patients with documented coronary artery disease and abnormal myocardial delayed enhancement (MDE) consistent with MI. A computer-assisted, semiautomatic algorithm quantified the total infarct size and divided it into the core and peri-infarct regions based on signal-intensity thresholds (>3 SDs and 2 to 3 SDs above remote normal myocardium, respectively). The peri-infarct zone was normalized as a percentage of the total infarct size (%MDE(periphery)). After a median follow-up of 2.4 years, 29 (20%) patients died. Patients with an above-median %MDE(periphery) were at higher risk for death compared with those with a below-median %MDE(periphery) (28% versus 13%, log-rank P<0.01). Multivariable analysis showed that left ventricular systolic volume index and %MDE(periphery) were the strongest predictors of all-cause mortality (adjusted hazard ratio [HR] for %MDE(periphery), 1.45 per 10% increase; P=0.002) and cardiovascular mortality (adjusted HR, 1.51 per 10% increase; P=0.009). Similarly, after adjusting for age and left ventricular ejection fraction, %MDE(periphery) maintained strong and independent associations with all-cause mortality (adjusted HR, 1.42; P=0.005) and cardiovascular mortality (adjusted HR, 1.49; P=0.01). CONCLUSIONS: In patients with a prior MI, the extent of the peri-infarct zone characterized by CMR provides incremental prognostic value beyond left ventricular systolic volume index or ejection fraction. Infarct characteristics by CMR may prove to be a unique and valuable noninvasive predictor of post-MI mortality.

Background: SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease. Methods: Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m 2 . The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide). Results: Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m 2 , LV mass indexed to body surface area 60.7 [11.9] g/m 2 ), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m 2 and 0.01 g/m 2 for those assigned empagliflozin and placebo, respectively (adjusted difference −3.35 g/m 2 ; 95% CI, −5.9 to −0.81g/m 2 , P =0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference −6.8mmHg, 95% CI −11.2 to −2.3mmHg, P =0.003), diastolic blood pressure (adjusted difference −3.2mmHg; 95% CI, −5.8 to −0.6mmHg, P =0.02) and elevation of hematocrit ( P =0.0003). Conclusions: Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02998970.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is markedly elevated in advanced heart failure. It is not known whether tissue TNF-alpha is elevated in the common setting of myocardial infarction leading to heart failure and what the source of TNF-alpha is. To determine this, we studied the expression and protein localization of TNF-alpha and its 2 main receptors (TNF-R1/R2) in a rat model of large infarction. METHODS AND RESULTS: Male rats were randomized to proximal left anterior descending ligation. The animals were killed on days 1, 3, 10, and 35 after ligation to examine gene expression and protein production of TNF-alpha and TNF-R1/R2 from the infarct, peri-infarct, and contralateral zones of infarcted heart. There was increased TNF-alpha mRNA production throughout the myocardium at day 1, and detectable expression persisted to day 35 after myocardial infarction. The expression of this cytokine is not confined strictly to the infarct or peri-infarct zones but is expressed by cardiac myocytes within the myocardium in the contralateral normal zone. Changes in gene expression are mirrored initially by augmented protein production within the myocytes. Levels of TNF-alpha protein in the infarct and peri-infarct zones rose early to 8- to 10-fold above normal levels and rose to 4- to 5-fold in the contralateral zone. Finally, expression of the TNF-R1 mRNA transcripts was upregulated at days 3 and 10 after ligation in the infarct and peri-infarct zones, suggesting that the signal transduction pathways necessary for TNF-alpha in the heart remain intact as TNF-alpha biosynthesis increases. CONCLUSIONS: TNF-alpha is present early in a model of large myocardial infarction and is sustained into the later stage within the myocardium. Expression of this cytokine is not only confined strictly to the infarct or peri-infarct zone but is expressed by cardiac myocytes within the myocardium contralateral to the infarct. Therefore TNF-alpha production forms a part of an important intrinsic myocardial stress response system to injury.

empagliflozin ◼ erythrocytes ◼ erythropoietin ◼ iron ◼ sodium-glucose transporter 2 inhibitors S odium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to improve cardiovascular outcomes, including hospitalization for heart failure and mortality, in people with and without diabetes mellitus. 1,2The mechanisms underlying this benefit remain unclear.Although several hypotheses have been suggested (including SGLT2 inhibitormediated diuresis and natriuresis, reduction in blood pressure and afterload, direct effects on myocardial sodium and calcium handling, alterations in myocardial energetics, reduction in left ventricular mass, and improved progenitor cell response), 3 a mediation analysis from the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) suggests that an increase in hematocrit may account for more than half of the mortality benefit observed.The consistent observation of an increase in hematocrit, even in those without diabetes mellitus, has led to the hypothesis that SGLT2 inhibitors may increase erythropoiesis via enhanced erythropoietin secretion by the kidney. 4This SGLT2 inhibitor-mediated increase in erythropoietin production (and resultant rise in hematocrit) could lead to systemic organ protection by virtue of its capacity as a circulating pleiotropic cytokine, known to favorably influence cardiomyocyte mitochondrial function, angiogenesis, cell proliferation, and inflammation.In addition, an increase in erythropoietin-induced hematocrit may improve myocardial function by directly enhancing myocardial and systemic tissue oxygen delivery.In this substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes) CardioLink-6 randomized clinical trial in which 6 months of empagliflozin treatment was associated with significant reduction in left ventricular mass index, 5 we measured erythropoietin levels, red blood cell (RBC) morphology, and indices of iron stores in individuals with type 2 diabetes mellitus and stable coronary artery disease who were randomized to either empagliflozin 10 mg daily or placebo for 6 months.The St Michael's Hospital Research Ethics Board approved the study, and all subjects gave informed consent.Blood samples were collected at baseline, after 1 month of treatment, and at the end of the study (6 months).Erythropoietin levels were measured from frozen sera with a 2-site immunoenzymatic chemiluminescent assay, and the data were analyzed with a linear mixed-effects model that included treatment group, visit, and treatment-by-visit interaction, and baseline values as fixed effects.Iron indices, ferritin, and complete blood counts were measured at baseline and at 6 months with standard spectrophotometric, 2-site immunoenzymatic, and flow cytometric techniques, with data analyzed using ANCOVA adjusted for baseline values.Values of P<0.05 were considered significant.

AIMS: Our objectives were (i) to compare the discriminatory performance of the Thrombolysis in Myocardial Infarction risk score (TIMI RS), Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy risk score (PURSUIT RS), and Global Registry of Acute Cardiac Events risk score (GRACE RS) for in-hospital and 1 year mortality across the broad spectrum of non-ST-elevation acute coronary syndromes (ACS) and (ii) to determine their incremental prognostic utility beyond overall risk assessment by physicians. METHODS AND RESULTS: We calculated the TIMI RS, PURSUIT RS, and GRACE RS for 1,728 patients with non-ST-elevation ACS in the prospective, multicentre, Canadian ACS II Registry. Discriminatory performance was measured by the c-statistic (area under receiver-operating characteristic curve) and compared by the method described by DeLong. TIMI RS, PURSUIT RS, and GRACE RS all demonstrated good discrimination for in-hospital death (c-statistics = 0.68, 0.80, 0.81, respectively, all P < 0.001) and 1 year mortality (c-statistics = 0.69, 0.77, 0.79, respectively, all P < 0.0001). However, PURSUIT RS and GRACE RS performed significantly better than the TIMI RS in predicting in-hospital (P = 0.036 and 0.02, respectively) and 1 year (P = 0.006 and 0.001, respectively) outcomes. In multivariable analysis adjusting for the use of in-hospital revascularization, stratification by tertiles of risk scores (into low, intermediate, and high-risk groups) furnished independent and greater prognostic information compared with risk assessment by treating physicians for 1 year outcome. CONCLUSION: Compared with TIMI RS, both PURSUIT RS and GRACE RS allow better discrimination for in-hospital and 1 year mortality in patients presenting with a wide range of ACS. All three risk scores confer additional important prognostic value beyond global risk assessment by physicians. These validated risk scores may refine risk stratification, thereby improving patient care in routine clinical practice.