Comparative Definitions for Moderate-Severe Ischemia in Stress Nuclear, Echocardiography, and Magnetic Resonance Imaging

The lack of standardized reporting of the magnitude of ischemia on noninvasive imaging contributes to variability in translating the severity of ischemia across stress imaging modalities. We identified the risk of coronary artery disease (CAD) death or myocardial infarction (MI) associated with \u3e= 10% ischemic myocardium on stress nuclear imaging as the risk threshold for stress echocardiography and cardiac magnetic resonance. A narrative review revealed that \u3e= 10% ischemic myocardium on stress nuclear imaging was associated with a median rate of CAD death or MI of 4.9%/year (interquartile range: 3.75% to 5.3%). For stress echocardiography, \u3e= 3 newly dysfunctional segments portend a median rate of CAD death or MI of 4.5%/year (interquartile range: 3.8% to 5.9%). Although imprecisely delineated, moderate-severe ischemia on cardiac magnetic resonance may be indicated by \u3e= 4 of 32 stress perfusion defects or \u3e= 3 dobutamine-induced dysfunctional segments. Risk-based thresholds can define equivalent amounts of ischemia across the stress imaging modalities, which will help to translate a common understanding of patient risk on which to guide subsequent management decisions. (C) 2014 by the American College of Cardiology Foundatio

Phosphomimetic Modulation of eNOS Improves Myocardial Reperfusion and Mimics Cardiac Postconditioning in Mice

Objective: Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection. Methods and Results: We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock-in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no-reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation. Conclusions and Significance: Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO.American Heart Association (Predoctoral Fellowship)National Institutes of Health (U.S.) (R01 NS33335)National Institutes of Health (U.S.) (R01 HL57818

Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis.

Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here, we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebrafish embryos reveal that wnt9b expression is similarly restricted to the endocardial cells overlying the developing heart valves and is dependent upon both hemodynamic shear forces and klf2a expression. These studies identify KLF2-WNT9B signaling as a conserved molecular mechanism by which fluid forces sensed by endothelial cells direct the complex cellular process of heart valve development and suggest that congenital valve defects may arise due to subtle defects in this mechanotransduction pathway.journal articleresearch support, non-u.s. gov'tresearch support, n.i.h., extramural2017 11 062017 10 19importe

Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab

BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10–1.71), P = 0.02; PlGF 3.78 (1.30–11.0), P = 0.047; GDF-15 1.71 (1.15–2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts

Comparative Definitions for Moderate-Severe Ischemia in Stress Nuclear, Echocardiography, and Magnetic Resonance Imaging

The lack of standardized reporting of the magnitude of ischemia on noninvasive imaging contributes to variability in translating the severity of ischemia across stress imaging modalities. We identified the risk of coronary artery disease (CAD) death or myocardial infarction (MI) associated with ≥10% ischemic myocardium on stress nuclear imaging as the risk threshold for stress echocardiography and cardiac magnetic resonance. A narrative review revealed that ≥10% ischemic myocardium on stress nuclear imaging was associated with a median rate of CAD death or MI of 4.9%/year (interquartile range: 3.75% to 5.3%). For stress echocardiography, ≥3 newly dysfunctional segments portend a median rate of CAD death or MI of 4.5%/year (interquartile range: 3.8% to 5.9%). Although imprecisely delineated, moderate-severe ischemia on cardiac magnetic resonance may be indicated by ≥4 of 32 stress perfusion defects or ≥3 dobutamine-induced dysfunctional segments. Risk-based thresholds can define equivalent amounts of ischemia across the stress imaging modalities, which will help to translate a common understanding of patient risk on which to guide subsequent management decisions