Arunima Misra

Nuclear Factor-κB Protects the Adult Cardiac Myocyte Against Ischemia-Induced Apoptosis in a Murine Model of Acute Myocardial Infarction

Background—Previous studies have shown that tumor necrosis factor (TNF) confers cytoprotective responses in cardiac myocytes. However, the mechanisms for the cytoprotective effects of TNF remain unknown. Given that TNF signals through nuclear factor &kgr;B (NF-&kgr;B) and given that NF-&kgr;B mediates cytoprotective responses, we asked whether NF-&kgr;B activation conferred cytoprotective responses in acute myocardial ischemia/infarction. Methods and Results—We examined infarct size and the prevalence of apoptosis in transgenic mice harboring cardiac-restricted expression of a mutated I&kgr;B&agr; protein (I&kgr;B&agr;&Dgr;N) that prevents nuclear translocation of NF-&kgr;B in cardiac myocytes. Triphenyltetrazolium chloride staining showed that infarct size was ≈50% greater (P <0.02) in the I&kgr;B&agr;&Dgr;N mice compared with littermate controls at 24 hours. The prevalence of cardiac myocyte apoptosis was significantly greater (P <0.008) in the I&kgr;B&agr;&Dgr;N mice compared with the littermate control mice 3 and 6 hours after left anterior descending occlusion. To explore the mechanism for these findings, we examined protein levels of c-IAP1, c-IAP2, and Bcl-2 as well as manganese superoxide dismutase and c-Jun NH2-terminal kinase activity. These studies showed that protein levels of c-IAP1 and Bcl-2 were significantly lower in the I&kgr;B&agr;&Dgr;N mice, whereas there was no change in c-IAP2 levels, manganese superoxide dismutase, or c-Jun NH2-terminal kinase activity. Conclusions—Transgenic mice with a defect in activation of NF-&kgr;B have increased susceptibility to tissue injury after acute left anterior descending occlusion. These studies suggest that the cytoprotective effects of NF-&kgr;B are mediated, at least in part, by Bcl-2 or c-IAP1.

CD14-Deficient Mice Are Protected Against Lipopolysaccharide-Induced Cardiac Inflammation and Left Ventricular Dysfunction

Background—The molecular mechanisms responsible for sepsis-induced myocardial dysfunction remain undefined. CD14 mediates the inflammatory response to lipopolysaccharide (LPS) in various organs including the heart. In this study we investigated the role of CD14 in LPS-induced myocardial dysfunction in vivo. Methods and Results—Wild-type and CD14-deficient (CD14-D) mice were challenged with Escherichia coli LPS. Myocardial tumor necrosis factor, interleukin-1&bgr; (IL-1&bgr;), and NOS2 induction was measured before and 6 hours after LPS challenge. Echocardiographic parameters of left ventricular function were measured before and 6 hours after LPS administration. LPS challenge induced a significant increase in myocardial tumor necrosis factor and IL-1&bgr; mRNA and protein expression in wild-type mice. In contrast, mRNA and protein levels for TNF and IL-1&bgr; were significantly blunted in CD14-D mice. An increase in NOS2 protein was noted within 6 hours of LPS provocation only in the hearts of wild-type mice. This was associated with an increase in ventricular cGMP levels. Activation of nuclear factor-&kgr;B was observed within 30 minutes of LPS in the hearts of wild-type mice but not in CD14-D mice. In wild-type mice, LPS significantly decreased left ventricular fractional shortening, velocity of circumferential shortening, and dP/dtmax. LPS-treated CD14-D mice maintained normal cardiac function. Conclusions—These results suggest that CD14 is important in mediating the proinflammatory response induced by LPS in the heart and that CD14 is necessary for the development of left ventricular dysfunction during LPS-induced shock in vivo.

Myotrophin/V-1, a Protein Up-regulated in the Failing Human Heart and in Postnatal Cerebellum, Converts NFκB p50-p65 Heterodimers to p50-p50 and p65-p65 Homodimers

Myotrophin/V-1 is a cytosolic protein found at elevated levels in failing human hearts and in postnatal cerebellum. We have previously shown that it disrupts nuclear factor of κB (NFκB)-DNA complexes in vitro. In this study, we demonstrated that in HeLa cells native myotrophin/V-1 is predominantly present in the cytoplasm and translocates to the nucleus during sustained NFκB activation. Three-dimensional alignment studies indicate that myotrophin/V-1 resembles a truncated IκBα without the signal response domain (SRD) and PEST domains. Co-immunoprecipitation studies reveal that myotrophin/V-1 interacts with NFκB proteinsin vitro; however, it remains physically associated only with p65 and c-Rel proteins in vivo during NFκB activation. In vitro studies indicate that myotrophin/V-1 can promote the formation of p50-p50 homodimers from monomeric p50 proteins and can convert the preformed p50-p65 heterodimers into p50-p50 and p65-p65 homodimers. Furthermore, adenovirus-mediated overexpression of myotrophin/V-1 resulted in elevated levels of both p50-p50 and p65-p65 homodimers exceeding the levels of p50-p65 heterodimers compared with Adβgal-infected cells, where the levels of p50-p65 heterodimers exceeded the levels of p50-p50 and p65-p65 homodimers. Thus, overexpression of myotrophin/V-1 during NFκB activation resulted in a qualitative shift by quantitatively reducing the level of transactivating heterodimers while elevating the levels of repressive p50-p50 homodimers. Correspondingly, overexpression of myotrophin/V-1 resulted in significantly reduced κB-luciferase reporter activity. Because myotrophin/V-1 is found at elevated levels during NFκB activation in postnatal cerebellum and in failing human hearts, this study cumulatively suggests that myotrophin/V-1 is a regulatory protein for modulating the levels of activated NFκB dimers during this period.

Postprandial effects on arterial stiffness parameters in healthy young adults

Postprandial lipemia has been associated with acute endothelial dysfunction. Endothelial dysfunction, in turn, is associated with increased arterial stiffness. However, the relationship between postprandial lipemia and acute changes in arterial stiffness has not been extensively investigated. Therefore, we conducted a pilot study on the effects of postprandial lipemia on arterial stiffness in 19 healthy young adults before and after consumption of a high-fat mixed meal. Arterial stiffness was assessed locally with echo-tracking carotid arterial strain (CAS) and globally with carotid–femoral pulse wave velocity (PWV). As assessed by these two benchmark parameters, arterial stiffness did not differ significantly postprandially. However, the arterial distension period (ADP) was significantly lower 2 hours after mixed meal ingestion. In addition, slopes of carotid artery area (CAA) curves were significantly steeper postprandially. Therefore, we concluded that ADP may be a more sensitive marker of arterial stiffness in healthy young adults when compared to PWV and CAS.

Persistent Left Superior Vena Cava: An Incidental Finding

![Figure][1] [![Graphic][3] ][3] A 29-year-old Hispanic man with palpitations was found to have a large and dilated coronary sinus (CS) on transthoracic echocardiogram ( A , [Online Video 1][3]). Agitated saline injected into the left antecubital vein opacified the CS and then the

Outcomes of beta blocker use in cocaine-associated chest pain: a meta-analysis

Objectives Beta blockers (β-blockers) remain a standard therapy in the early treatment of acute coronary syndromes. However, β-blocker therapy in patients with cocaine-associated chest pain (CACP) continues to be an area of debate due to the potential risk of unopposed α-adrenergic stimulation and coronary vasospasm. Therefore, we performed a systematic review and meta-analysis of available studies to compare outcomes of β-blocker versus no β-blocker use among patients with CACP. Methods We searched the MEDLINE and EMBASE databases through September 2016 using the keywords ‘beta blocker’, ‘cocaine’ and commonly used β-blockers (‘atenolol’, ‘bisoprolol’, ‘carvedilol’, ‘esmolol’, ‘metoprolol’ and ‘propranolol’) to identify studies evaluating β-blocker use among patients with CACP. We specifically focused on studies comparing outcomes between β-blocker versus no β-blocker usage in patients with CACP. Studies without a comparison between β-blocker and no β-blocker use were excluded. Outcomes of interest included non-fatal myocardial infarction (MI) and all-cause mortality. Quantitative data synthesis was performed using a random-effects model and heterogeneity was assessed using Q and I2statistics. Results A total of five studies evaluating 1794 subjects were included. Overall, there was no significant difference on MI in patients with CACP on β-blocker versus no β-blocker (OR 1.36, 95% CI 0.68 to 2.75; p=0.39). Similarly, there was no significant difference in all-cause mortality in patients on β-blocker versus no β-blocker (OR 0.68, 95% CI 0.26 to 1.79; p=0.43). Conclusions In patients presenting with acute chest pain and underlying cocaine, β-blocker use does not appear to be associated with an increased risk of MI or all-cause mortality.

NT-proBNP–guided and conventional therapies did not differ for readmission or mortality in acute decompensated HF

Question In stabilized patients hospitalized for acute decompensated heart failure (ADHF), does N-terminal-pro-B-type natriuretic peptide (NT-proBNP)-guided therapy reduce readmission and mortality? Methods Design Randomized controlled trial (Can NT-ProBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions? [PRIMA II] trial). Nederlands Trial Register NTR3279. Allocation {Concealed}*. Blinding Blinded (outcome adjudicators and {data safety monitoring committee}*). Follow-up period 180 days. Setting 11 clinical centers in Holland, Portugal, and Spain. Patients 405 patients (mean age 77 y, 51% women) who were admitted for ADHF, had NT-proBNP levels >1700 ng/L (>200 pmol/L) within 24 hours of admission, and had achieved clinical stability (after hospitalization for 3 d, achieved 3 of target weight reached, stable serum creatinine level [<25% increase from baseline], improved symptoms and mobilization was possible, and adequate discharge medication prescribed). Exclusion criteria included severe comorbidities or planned coronary artery bypass grafting, percutaneous coronary intervention, valvular surgery, or cardiac resynchronization therapy. Intervention NT-proBNP-guided therapy (n =202) or conventional therapy (n =203). NT-proBNP was measured on the day of randomization. In the NT-proBNP group, discharge and follow-up were planned for patients with >30% decrease in levels from admission. Patients with NT-proBNP reductions 30% followed an algorithm comprising additional NT-proBNP measurements; titration of HF medication; and such invasive therapies as implantation of cardiac resynchronization, diagnostic coronary angiography, and electric conversion. In the conventional therapy group, NT-proBNP measurements at randomization were not given to physicians; discharge and follow-up of patients were determined by treating physicians. Outcomes Co-primary outcomes were a composite of readmission for HF or all-cause mortality at 180 days after randomization, and number of days alive out of hospital at 180 days after discharge. Secondary outcomes included components of the composite outcome. 400 patients provided 80% power to detect an amended relative risk reduction of 27% in the primary composite outcome from an estimated 50% event rate in the conventional therapy group (2-sided =0.05). Patient follow-up 99.8% (intention-to-treat analysis). Main results NT-proBNP-guided and conventional therapy did not differ for the median number of days alive outside of the hospital at 180 days (178 vs 179, P =0.39). Other outcomes are in the Table. Conclusion In stabilized patients hospitalized for acute decompensated heart failure, N-terminal-proB-type natriuretic peptideguided therapy using a predefined target (>30% reduction) did not reduce readmission or mortality compared with conventional therapy. NT-proBNP-guided therapy vs conventional therapy in stabilized patients admitted for acute decompensated heart failure (HF) Outcomes Event rates At 180 d NT-proBNP Conventional RRR (95% CI) Composite of readmission for HF or all-cause mortality 36% 36% 3% (27 to 24) Readmission for HF 24% 26% 6% (31 to 34) RRI (CI) All-cause mortality 19% 17% 11% (27 to 65) NT-proBNP = N-terminal-pro-B-type natriuretic peptide; other abbreviations defined in Glossary. RRR, RRI, and CI calculated from conventional therapy event rates and hazard ratios in article. Commentary The 2017 update of the American Heart Association/American College of Cardiology/Heart Failure Society of America HF guideline does not recommend the use of target natriuretic peptide levels to guide therapy in acute or chronic HF (1). Results of the well-designed PRIMA II trial do not support use of NT-proBNP-guided therapy in hospitalized HF patients who have achieved clinical stability with conventional medical therapy. About 64% of PRIMA II patients in both groups achieved the target >30% reduction in NT-proBNP levels with initial therapy by the time they reached clinical stability. This reduced the power to observe differences between groups and underscores the effectiveness of initial therapy for all patients; post hoc subgroup analysis of the 133 patients who did not achieve the target with initial therapy was underpowered and did not find a difference in the primary outcome between guided and conventional therapy at 6 months (49% vs 55%, P =0.5). The 61% reduction in NT-proBNP levels in patients requiring no further intervention during hospitalization may suggests a need for a greater targeted reduction in the NT-proBNP-guided group to show benefit in some patients; however, further investigation is needed to understand the 19% of patients who did not achieve even a 30% reduction despite biomarker-guided therapy. PRIMA II reconfirmed the prognostic value of achieved natriuretic peptide level reduction. In a post hoc analysis, patients who did not achieve >30% reduction with the guided strategy had the poorest outcomes at 6 months, followed by patients with guided reductions >30%; patients who achieved the target reduction without biomarker guidance had the best outcomes.

Heart failure education in the emergency department markedly reduces readmissions in un- and under-insured patients

Background: Heart failure (HF) readmissions are a longstanding national healthcare issue for both hospitals and patients. Our purpose was to evaluate the efficacy of a structured, educational intervention targeted towards un‐ and under‐insured emergency department (ED) HF patients. Methods: HF patients presenting to the ED for care were enrolled between July and December 2015 as part of an open label, interventional study, using a parallel observational control group. Eligible patients provided informed consent, had an established HF diagnosis, and were hemodynamically stable. Intervention patients received a standardized educational intervention in the ED waiting room before seeing the emergency physician, and a 30‐day telephone follow‐up. Primary and secondary endpoints were 30‐ and 90‐day ED and hospital readmission rates, as well as days alive and out of hospital (DAOH) respectively. Results: Of the 94 patients enrolled, median age was 58.4 years; 40.4% were female, and 54.3% were African American. Intervention patients (n = 45) experienced a 47.8% and 45.3% decrease in ED revisits (P = 0.02 & P < 0.001), and 60.0% and 47.4% decrease in hospital readmissions (P = 0.049 & P = 0.007) in the 30 and 90 days pre‐ versus post‐intervention respectively. Control patients (n = 49) had no change in hospital readmissions or 30‐day ED revisits, but experienced a 36.6% increase in 90‐day ED revisits (P = 0.03). Intervention patients also saw a 59.2% improvement in DAOH versus control patients (P = 0.03). Conclusion: An ED educational intervention markedly decreases ED and hospital readmissions in un‐ and under‐insured HF patients.

EDUCATIONAL STRATEGY FOR MANAGEMENT OF HEART FAILURE MARKEDLY REDUCES 90-DAY EMERGENCY DEPARTMENT AND HOSPITAL READMISSIONS IN UN- AND UNDERINSURED PATIENTS

Background: Previous studies report conflicting results on the effectiveness of educational intervention in patients with heart failure (HF). The purpose of this pilot study was to evaluate the efficacy of a structured educational intervention targeted towards un- and underinsured patients

SEGMENTAL ANALYSIS OF CIRCUMFERENTIAL SYSTOLIC CAROTID ARTERIAL STRAIN IN DIABETICS AND HYPERTENSIVES USING 2D SPECKLE TRACKING

Results: Baseline characteristics were similar among groups except heart rate and hypertension (Table). Mean far wall and global CAS were lower in diabetics and hypertensives than in controls. There was no difference between diabetics and hypertensives (Table). When pooled (n=61), age, heart rate and hypertension were predictors of low global net (p=0.001, p=0.02, p=0.02, respectively) and mean far wall CAS (p=0.02 for all 3 variables). Though small (n=5), CAS in non-hypertensive diabetics was similar to hypertensive diabetics. Conventional lumen CAS was similar among all groups.