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Background Adults presenting with an unrepaired atrial septal defect and pulmonary arterial hypertension (ASD-PAH) are typically classified as “correctable” or “non-correctable”. The use of directed PAH medical therapy in non-correctable ASD-PAH leading to favorable closure candidacy, repair status and long-term follow-up is not well studied. We therefore sought to characterize response to PAH targeted therapy in ‘non-correctable’ ASD-PAH. Methods and results Nine North American tertiary care centers submitted retrospective data from adults with unrepaired ASD-PAH that did not meet recommendations for repair at initial presentation (1996–2017). Sixty-nine patients (women 51(74%), 40 ± 15 years, mean pulmonary artery pressure (mPA) 51 ± 13 mm Hg, pulmonary vascular resistance (PVR) 8.7 ± 4.9 Wood units, Qp:Qs 1.6 ± 0.4) were enrolled. All patients were prescribed PAH targeted therapy and late shunt repair occurred in 19(28%) (Women 15(29%) vs. Men 4(22%), p = 0.6). At late follow-up (4.4 ± 2.9 years) 6-minute walk test distance (6MWTD) was significantly better in the group that underwent repair (486 ± 89 m vs. 375 ± 139 m, p Conclusions This is the first and largest multicenter study evaluating the “treat-to-close” approach in non-correctable ASD-PAH. Our new data supports further study of this strategy in patients who have reversibility of PAH in response to targeted therapy. We demonstrate that in the carefully selected patient with non-correctable ASD-PAH, successful shunt repair is possible if post-therapy PVR is ≤6.5 Wood units. Patients who underwent repair had improved RV function following PAH targeted therapy. Divergent survival curves suggest that with further study, defect repair may affect medium-term to late survival.

Aim TAVR in patients with bicuspid aortic valves (BAV) is more challenging compared to individuals with trileaflet aortic valves (TAV). BAV have been excluded from the large randomized clinical trials assessing transcatheter aortic valve replacements (TAVR) and has been considered as a relative contraindication to TAVR. To report the outcomes of TAVR in BAV and compare them to TAV in the National Inpatient Sample (NIS). Methods and results TAVR procedures were identified between 2011 and 2014 in the NIS dataset. Endpoints assessed included in-hospital mortality, periprocedural complications, length of stay and cost. Of 40,604 identified TAVR procedures, 407 (1%) were BAV and the 40,197 (99%) were TAV. Patients with BAV were younger and had a lower comorbidity burden. In hospital mortality (4.89% vs 4.17%, OR: 1.71, 95%CI: 0.57–5.12, P = 0.21), AMI (3.49% vs 3.58%, OR: 1.12, 95%CI: 0.36–3.54, P = 0.85), stroke and TIA (2.49% vs 3.55%, OR: 0.75, 95%CI: 0.18–3.16, P = 0.70), vascular complications (2.39% vs 5.58%, OR:0.47, 95%CI: 0.11–1.93, P = 0.29), major bleeding (16.96% vs 23.50%, OR: 0.63, 95%CI: 0.34–1.17, P = 0.15) and rates of permanent pacemaker (PPM) (9.88% vs 10.88%, OR: 1.19, 95%CI: 0.57–2.51, P = 0.64) were similar in both cohorts. Conclusions With multimodality imaging and further improvement in technology, our study demonstrates off-label TAVR should not be considered prohibitive and can be successfully performed for BAV with similar peri-procedural outcomes compared to those with TAV. However, there is a need for robust large prospective studies.

The aim of this study was to evaluate the combined impact of race, ethnicity, and sex on in-hospital outcomes using data from the National Inpatient Sample.Cardiogenic shock (CS) is a major cause of mortality following ST-segment elevation myocardial infarction (STEMI). Early revascularization reduces mortality in such patients. Mechanical circulatory support (MCS) devices are increasingly used to hemodynamically support patients during revascularization. Little is known about racial, ethnic, and sex disparities in patients with STEMI and CS.The National Inpatient Sample was queried from January 2006 to September 2015 for hospitalizations with STEMI and CS. The associations between sex, race, ethnicity, and outcomes were examined using complex-samples multivariate logistic or generalized linear model regressions.Of 159,339 patients with STEMI and CS, 57,839 (36.3%) were women. In-hospital mortality was higher for all women (range 40% to 45.4%) compared with men (range 30.4% to 34.7%). Women (adjusted odds ratio [aOR]: 1.11; 95% confidence interval [CI]: 1.06 to 1.16; p 0.001) as well as Black (aOR: 1.18; 95% CI: 1.04 to 1.34; p = 0.011) and Hispanic (aOR: 1.19; 95% CI: 1.06 to 1.33; p = 0.003) men had higher odds of in-hospital mortality compared with White men, with Hispanic women having the highest odds of in-hospital mortality (aOR: 1.46; 95% CI: 1.26 to 1.70; p 0.001). Women were older (age: 69.8 years vs. 63.2 years), had more comorbidities, and underwent fewer invasive cardiac procedures, including revascularization, right heart catheterization, and MCS.There are significant racial, ethnic, and sex differences in procedural utilization and clinical outcomes in patients with STEMI and CS. Women are less likely to undergo invasive cardiac procedures, including revascularization and MCS. Women as well as Black and Hispanic patients have a higher likelihood of death compared with White men.

Objective Patients with autoimmune rheumatic disease (AIRD) are at an increased risk of coronary artery disease. The present study sought to examine the prevalence and outcomes of AIRD patients undergoing percutaneous coronary intervention (PCI) from a national perspective. Methods All PCI-related hospitalizations recorded in the US National Inpatient Sample (2004–2014) were included, stratified into four groups: no AIRD, RA, SLE and SSc. We examined the prevalence of AIRD subtypes and assessed their association with in-hospital adverse events using multivariable logistic regression [odds ratios (OR) (95% CI)]. Results Patients with AIRD represented 1.4% (n = 90 469) of PCI hospitalizations. The prevalence of RA increased from 0.8% in 2004 to 1.4% in 2014, but other AIRD subtypes remained stable. In multivariable analysis, the adjusted odds ratio (aOR) of in-hospital complications [aOR any complication 1.13 (95% CI 1.01, 1.26), all-cause mortality 1.32 (1.03, 1.71), bleeding 1.50 (1.30, 1.74), stroke 1.36 (1.14, 1.62)] were significantly higher in patients with SSc compared with those without AIRD. There was no difference in complications between the SLE and RA groups and those without AIRD, except higher odds of bleeding in SLE patients [aOR 1.19 (95% CI 1.09, 1.29)] and reduced odds of all-cause mortality in RA patients [aOR 0.79 (95% CI 0.70, 0.88)]. Conclusion In a nationwide cohort of US hospitalizations, we demonstrate increased rates of all adverse clinical outcomes following PCI in people with SSc and increased bleeding in SLE. Management of such patients should involve a multiteam approach with rheumatologists.

Aims This study aims to examine the temporal trends and outcomes in patients who undergo percutaneous coronary intervention (PCI) with a previous or current diagnosis of cancer, according to cancer type and the presence of metastases. Methods and results Individuals undergoing PCI between 2004 and 2014 in the Nationwide Inpatient Sample were included in the study. Multivariable analyses were used to determine the association between cancer diagnosis and in-hospital mortality and complications. 6 571 034 PCI procedures were included and current and previous cancer rates were 1.8% and 5.8%, respectively. Both rates increased over time and the four most common cancers were prostate, breast, colon, and lung cancer. Patients with a current lung cancer had greater in-hospital mortality (odds ratio (OR) 2.81, 95% confidence interval (95% CI) 2.37–3.34) and any in-hospital complication (OR 1.21, 95% CI 1.10–1.36), while current colon cancer was associated with any complication (OR 2.17, 95% CI 1.90–2.48) and bleeding (OR 3.65, 95% CI 3.07–4.35) but not mortality (OR 1.39, 95% CI 0.99–1.95). A current diagnosis of breast was not significantly associated with either in-hospital mortality or any of the complications studied and prostate cancer was only associated with increased risk of bleeding (OR 1.41, 95% CI 1.20–1.65). A historical diagnosis of lung cancer was independently associated with an increased OR of in-hospital mortality (OR 1.65, 95% CI 1.32–2.05). Conclusions Cancer among patients receiving PCI is common and the prognostic impact of cancer is specific both for the type of cancer, presence of metastases and whether the diagnosis is historical or current. Treatment of patients with a cancer diagnosis should be individualized and involve a close collaboration between cardiologists and oncologists.

Frail patients are more prone to adverse events after cardiac surgery, particularly after implantation of left ventricular assist devices. Thus, frailty assessment may help identify patients unlikely to benefit from left ventricular assist device therapy. The purpose was to establish a suitable measure of frailty in adults with end-stage heart failure. In a prospective cohort of 75 patients (age 58 ± 12 years) with end-stage heart failure, we assessed the association between frailty (5-component Fried criteria) and the composite primary outcome of inpatient mortality or prolonged length of stay, as well as extubation status, time on ventilator, discharge status, and long-term mortality. Fried frailty criteria were met in 44 (59%) patients, but there was no association with the primary outcome (p = 0.10). However, an abridged set of 3 criteria (exhaustion, inactivity, and grip strength) was predictive of the primary outcome (odds ratio 2.9, 95% confidence interval 1.1 to 7.4), and of time to extubation and time to discharge. In patients with advanced heart failure, the 5-component Fried criteria may not be optimally sensitive to clinical differences. In conclusion, an abridged set of 3 frailty criteria was predictive of the primary outcome and several secondary outcomes, and may therefore be a clinically useful tool in this population.

OBJECTIVE: \ud This study aims to investigate the temporal trends in utilization of invasive coronary angiography (CA) at different time points and changing profiles of patients undergoing CA following non-ST-elevation acute coronary syndrome (NSTEACS). We also describe the association between timing of CA and in-hospital clinical outcomes.\ud \ud PATIENTS AND METHODS: \ud We queried the National Inpatient Sample to identify all admissions with a primary diagnosis of NSTEACS from 2004 to 2014. Patients were stratified into early (day 0, 1), intermediate (day 2) and late strategy (day≥3) according to timing of CA. Multivariable logistic regression was used to investigate the association between timing of CA and in-hospital mortality, major bleeding, stroke and Major Adverse Cardiac and Cerebrovascular Events. \ud \ud RESULTS: \ud A total of 4 380 827 records were identified with a diagnosis of NSTEACS, out of which 57.5% received CA. The proportion of patients undergoing early CA increased from 65.6 to 72.6%, whereas late CA commensurately declined from 19.6 to 13.5%. Patients receiving early CA were younger (age: 64 vs. 70 years), more likely to be male (63.7 vs. 55.3%) and of Caucasian ethnic background (68.7 vs. 64.7%) compared with late CA group. Similarly, Women, weekend admissions and African Americans remain less likely to receive early CA. In-hospital mortality was lowest in the intermediate group (odds ratio=0.30, 95% confidence interval: 0.28-0.33).\ud \ud CONCLUSION: Use of early CA has increased in the management of NSTEACS; however, there remain significant disparities in utilization of an early invasive approach in women, African Americans, admission day and older patients in the USA.

Introduction Exercise (ESE) and dobutamine stress echocardiography (DSE) have high sensitivity and specificity to detect inducible myocardial ischemia in patients with significant coronary artery disease (CAD). High-sensitivity cardiac troponin (hs-cTn) assays detect troponin concentrations in the ng/L range. The aim of this study was to determine the kinetics of hs-cTnT in patients undergoing ESE and DSE and possible association of hs-cTnT with inducible myocardial ischemia. Methods In this prospective study adult patients undergoing ESE/DSE were enrolled. Peripheral blood samples were obtained before, and 30 min, 1, 2, and 4–6 h after completion of ESE/DSE. Hs-cTnT was measured on a Roche Diagnostics Elecsys 2010 analyzer. Results We enrolled 48 patients (33 ESE and 15 DSE); 11 patients (23%) had elevated baseline hs-cTnT concentrations >14 ng/L (99th percentile URL); 31/48 (65%) developed an hs-cTnT increase after ESE/DSE (peak 4–6 h post stress test), but only three patients (all in ESE group) had a positive stress test. Absolute and relative hs-cTnT increases were higher after DSE (median Δhs-cTnT +9.7 ng/L [IQR 4.5, 27.2]; +123% [IQR 49, 271]) compared to ESE (median Δhs-cTnT +2.3 ng/L [IQR 1, 4.9]; +37% [IQR 9.1, 221]). Conclusions One in four patients undergoing ESE/DSE had increased hs-cTnT values prior to stress testing. Hs-cTnT increased above the upper limit of normal occurred commonly after ESE/DSE but was more pronounced after DSE. Increases in hs-cTn did not appear to be associated with inducible myocardial ischemia. These findings may have important implications for the clinical use of hs-cTnT within 6 h after ESE/DSE.

Adults presenting with an unrepaired atrial septal defect and pulmonary arterial hypertension (ASD-PAH) are typically classified as "correctable" or "non-correctable". The use of directed PAH medical therapy in non-correctable ASD-PAH leading to favorable closure candidacy, repair status and long-term follow-up is not well studied. We therefore sought to characterize response to PAH targeted therapy in 'non-correctable' ASD-PAH.Nine North American tertiary care centers submitted retrospective data from adults with unrepaired ASD-PAH that did not meet recommendations for repair at initial presentation (1996-2017). Sixty-nine patients (women 51(74%), 40 ± 15 years, mean pulmonary artery pressure (mPA) 51 ± 13 mm Hg, pulmonary vascular resistance (PVR) 8.7 ± 4.9 Wood units, Qp:Qs 1.6 ± 0.4) were enrolled. All patients were prescribed PAH targeted therapy and late shunt repair occurred in 19(28%) (Women 15(29%) vs. Men 4(22%), p = 0.6). At late follow-up (4.4 ± 2.9 years) 6-minute walk test distance (6MWTD) was significantly better in the group that underwent repair (486 ± 89 m vs. 375 ± 139 m, p 0.05). Transthoracic echo showed significant improvement in right ventricular (RV) function (severe dysfunction in repaired 8(40%) vs. unrepaired groups 35(69%), p 0.05). Divergent survival curves suggest that with larger studies and more follow-up, differences in survival between repaired and unrepaired groups may be important. (repaired: 17(94%) vs. unrepaired: 32(81%), p = 0.18).This is the first and largest multicenter study evaluating the "treat-to-close" approach in non-correctable ASD-PAH. Our new data supports further study of this strategy in patients who have reversibility of PAH in response to targeted therapy. We demonstrate that in the carefully selected patient with non-correctable ASD-PAH, successful shunt repair is possible if post-therapy PVR is ≤6.5 Wood units. Patients who underwent repair had improved RV function following PAH targeted therapy. Divergent survival curves suggest that with further study, defect repair may affect medium-term to late survival.

It is unclear how comorbidity influences rates and causes of unplanned readmissions following percutaneous coronary intervention (PCI). We analyzed patients in the Nationwide Readmission Database who were admitted to hospital between 2010 and 2014. The comorbidity burden as defined by the Charlson Comorbidity Index (CCI). Primary outcomes were 30-day readmission rates and causes of readmission according to comorbidity burden. A total of 2,294,346 PCI procedures were included the analysis. The patients in CCI = 0, 1, 2 and ≥3 were 842,272(36.7%), 701,476(30.6%), 347,537(15.1%) and 403,061(17.6%), respectively. 219,227(9.6%) had an unplanned readmission within 30 days and rates by CCI group were 6.6%, 8.6%, 11.4% and 15.9% for CCI groups 0, 1, 2 and ≥3, respectively. The CCI score was also associated with greater cost (cost of index PCI for not readmitted vs readmitted was CCI = 0 $21,257 vs $19,764 and CCI ≥ 3 $26,736 vs $27,723). Compared to patients with CCI = 0, greater CCI score was associated with greater independent odds of readmission (CCI = 1 OR 1.25(1.22–1.28), p

PURPOSE OF REVIEW: Peripheral arterial disease (PAD) is the third most common manifestation of cardiovascular disease (CVD), following coronary artery disease (CAD) and stroke. PAD remains underdiagnosed and under-treated in women.RECENT FINDINGS: Women with PAD experience more atypical symptoms and poorer overall health status. The prevalence of PAD in women increases with age, such that more women than men have PAD after the age of 40 years. There is under-representation of PAD patients in clinical trials in general and women in particular. In this article, we address the lack of women participants in PAD trials. We then present a comprehensive overview of the epidemiology/risk factor profile, clinical features, treatment, and outcomes. PAD is prevalent in women and its global burden is on the rise despite a decline in global age-standardized death rate from CVD. The importance of this issue has been underlined by the American Heart Association's (AHA) "Call to Action" scientific statement on PAD in women. Large-scale campaigns are needed to increase awareness among physicians and the general public. Furthermore, effective treatment strategies must be implemented.

Background\ud Prior studies have reported inconsistencies in the baseline risk profile, comorbidity burden and their association with clinical outcomes in women compared to men. More importantly, there is limited data around the sex differences and how these have changed over time in contemporary percutaneous coronary intervention (PCI) practice.\ud \ud Methods and results\ud We used the Nationwide Inpatient Sample to identify all PCI procedures based on ICD-9 procedure codes in the United States between 2004–2014 in adult patients. Descriptive statistics were used to describe sex-based differences in baseline characteristics and comorbidity burden of patients. Multivariable logistic regressions were used to investigate the association between these differences and in-hospital mortality, complications, length of stay and total hospital charges. Among 6,601,526 patients, 66% were men and 33% were women. Women were more likely to be admitted with diagnosis of NSTEMI (non-ST elevation acute myocardial infarction), were on average 5 years older (median age 68 compared to 63) and had higher burden of comorbidity defined by Charlson score ≥3. Women also had higher in-hospital crude mortality (2.0% vs 1.4%) and any complications compared to men (11.1% vs 7.0%). These trends persisted in our adjusted analyses where women had a significant increase in the odds of in-hospital mortality men (OR 1.20 (95% CI 1.16,1.23) and major bleeding (OR 1.81 (95% CI 1.77,1.86).\ud \ud Conclusion\ud In this national unselected contemporary PCI cohort, there are significant sex-based differences in presentation, baseline characteristics and comorbidity burden. These differences do not fully account for the higher in-hospital mortality and procedural complications observed in women.

OBJECTIVE Obesity affects adults with congenital heart disease (CHD). The effect of an increased body mass index (BMI) with respect to morbidity and mortality has not been evaluated in adults with complex CHD. Our objective was to evaluate the effects of increased BMI on heart failure and mortality in univentricular patients who had undergone Fontan palliation. METHODS A query of Fontan patients' first appointments at the Washington University Center for Adults with CHD between 2007 and 2014 yielded 79 patients. BMI status as normal (

A 19-year-old woman was noted on an incidental chest radiograph to have dextroposition of the heart secondary to a hypoplastic right lung, with a linear opacity to the right of the right atrium extending below the diaphragm (Fig. 1). Although the patient was asymptomatic, a subcostal view via transthoracic echocardiography showed substantial dilation of the right atrium and right ventricle, a pulmonary artery systolic pressure of 27 mmHg, and an abnormal vessel and flow entering a dilated inferior vena cava (IVC) (Fig. 2). Subsequent cardiac catheterization and angiography of the right pulmonary artery revealed complete anomalous right pulmonary venous (PV) drainage from the right lung to the infradiaphragmatic IVC with a pulmonic-to-systemic flow ratio (Qp:Qs) of 2.11:1 (Fig. 3). Cardiac magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) were performed before and after gadofosveset-trisodium contrast administration. This noninvasive study revealed anomalous drainage of the entire right lung into the infrahepatic IVC with a calculated Qp:Qs ratio of 2.1:1, confirmed the prior results, and suggested no anomalous pulmonary arterial supply, left PV drainage, horseshoe lung, or accessory diaphragm (Fig. 4). Because of substantial shunting, the scimitar right PV was repaired by means of an end-to-side anastomosis of the right PV to the left atrium adjacent to the atrial septum (Fig. 5). An outpatient postoperative MRI revealed the surgical connection, a decrease in right ventricular cavity size, and a Qp:Qs of 1:1 (Fig. 6). Postoperatively, the patient did well. Fig. 1. Frontal chest radiograph shows a hypoplastic lung with cardiac dextroposition and a linear opacity to the right of the atrium, extending below the diaphragm (arrows). Fig. 2. Transthoracic echocardiogram in color-flow Doppler mode (subcostal view) shows Doppler inflow (red) of the anomalous right pulmonary vein as it drains into the inferior vena cava. Fig. 3. Right pulmonary arteriogram (anteroposterior projection) shows anomalous pulmonary venous drainage of contrast medium into the inferior vena cava, inferior to the diaphragm (arrows). Fig. 4. Cardiac magnetic resonance image with contrast medium (posterior view in 3-dimensional rendering) defines the entire right pulmonary venous drainage to the infrahepatic inferior vena cava (arrows). Fig. 5. Postoperative frontal chest radiograph shows sternotomy wires and an unchanged heart size, with the cardiac apex lying to the right of the midline. Note the small basilar atelectasis. Fig. 6. Cardiac magnetic resonance angiograms with contrast medium. A) Anterior view shows the surgical connection between the right pulmonary vein and the left atrium. B) Posterior view, in 3-dimensional rendering. Note the postoperative changes associated with ...

Background Electrocardiograms (ECGs) are routinely obtained in patients with advanced congestive heart failure (CHF) before and after surgical implantation with a left-ventricular assist device (LVAD). As the number of patients with CHF is increasing, it is necessary to characterize the changes present in the ECG of patients with LVADs. Methods ECGs of 43 patients pre- and postimplantation of a HeartMate II LVAD were compared to characterize the presence of an LVAD using the following six criteria (LVADS2): low limb-lead voltage, ventricular pacing, artifact (electrical), duration of the QRS > 120 milliseconds, ST-elevation in the lateral leads, and splintering of the QRS complex. Additionally, 50 ECGs of non-LVAD patients coded as “lateral myocardial infarction (MI)” and 50 ECGs coded as “ventricular pacing” were chosen at random and scored. Odds ratios were calculated using Fisher's exact test. Logistic regression models were built to predict the presence of an LVAD in all patients. Results Univariate analysis of the pre- and post-LVAD ECGs confirmed that all criteria except the “Duration of QRS > 120 milliseconds” characterized the ECG of a patient with an LVAD. Electrical artifact and low limb-lead voltage yielded the greatest association with an LVAD-ECG. Conclusions The ECG of a patient with end-stage CHF significantly changes with LVAD implantation. The LVADS2 criteria provide a framework towards characterizing and establishing a new baseline of the ECG in a patient with a continuous-flow LVAD.

Left ventricular assist device (LVAD)-supported patients are evaluated routinely with use of transthoracic echocardiography. Values of left ventricular unloading in this unique patient population are needed to evaluate LVAD function and assist in patient follow-up. We introduce a new M-mode measurement, the slope of the anterior mitral valve leaflet (SLAM), and compare its efficacy with that of other standard echocardiographically evaluated values for left ventricular loading, including E/e′ and pulmonary artery systolic pressures. Average SLAM values were determined retrospectively for cohorts of random, non-LVAD patients with moderately to severely impaired left ventricular ejection fraction (LVEF) ( The average SLAM in patients with an LVEF Evaluating ventricular unloading in LVAD patients remains challenging. Our novel M-mode value correlates with echocardiographic values of left ventricular filling in patients with moderate-to-severe systolic function and dynamically improves with the ventricular unloading of an LVAD.

There is limited data around temporal changes in clinical characteristics of patients admitted with Non-ST elevation acute myocardial infarction (NSTEMI) receiving invasive coronary angiography (CA) at different time points and clinical outcomes. This study aims to investigate the temporal trends in

Diabetic patients with coronary artery disease are common and complex, with an aggressive progression of atherosclerosis, increased rate of stent complications, and increased rates of incomplete revascularization in multivessel disease compared to non-diabetic patients. In this review, we first discuss the pathophysiologic elements of insulin resistance and presentations of coronary artery disease in diabetic patients. Next, we outline the evolution and present the data on revascularization strategies on diabetic patient outcomes. The overall conclusion of our review is that a strategy of complete and durable revascularization and guideline-directed medical therapy currently provides the best possible chance at closing the gap between outcomes in patients with and without diabetes.

OBJECTIVE—β-Cells are particularly susceptible to fatty acid–induced apoptosis associated with decreased insulin receptor/phosphatidylinositol-3 kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of fatty acid–induced apoptosis of mouse β-cells especially as related to the role played by endoplasmic reticulum (ER) stress–induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival.RESEARCH DESIGN AND METHODS—Mouse insulinoma (MIN6) cells were administered with fatty acids, and the role of Foxo1 in mediating effects on signaling pathways and apoptosis was examined by measuring Foxo1 activity and using dominant-negative Foxo1.RESULTS—Increasing fatty acid concentrations (100–400 μmol/l palmitate or oleate) led to early Jun NH2-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with fatty acid administration and by pharmacological inducers of ER stress, and this increase was prevented by JNK inhibition. Fatty acids induced nuclear localization of Foxo1 at 4 h when Akt activity was increased, indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, fatty acid administration for 24 h was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and fatty acid–mediated apoptosis. Microarray analysis revealed that fatty acid induction of gene expression was in most cases reversed by Adv-DNFoxo, including the proapoptotic transcription factor CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein).CONCLUSIONS—Early induction of JNK and Foxo1 activation plays an important role in fatty acid–induced apoptosis. Expressing a dominant-negative allele of Foxo1 reduces expression of apoptotic and ER stress markers and promotes β-cell survival from fatty acid and ER stress, identifying a potential therapeutic target for preserving β-cells in type 2 diabetes.

Obesity affects adults with congenital heart disease (CHD). The effect of an increased body mass index (BMI) with respect to morbidity and mortality has not been evaluated in adults with complex CHD. Our objective was to evaluate the effects of increased BMI on heart failure and mortality in univentricular patients who had undergone Fontan palliation.A query of Fontan patients' first appointments at the Washington University Center for Adults with CHD between 2007 and 2014 yielded 79 patients. BMI status as normal (25 kg/m(2) ), overweight (≥25,30 kg/m(2) ), and obese (≥30 kg/m(2) ) was established at the patient's first appointment. We analyzed demographics, diuretic requirements, New York Heart Association (NYHA) class, and laboratory values using Student's two-sample t-test and Fisher's exact test. Mortality was assessed via survival curves, and hazard ratios were compiled with proportional hazard modeling.The recent average BMI was significantly greater in patients with NYHA classes II-IV (29.3 ± 9 kg/m(2) ) compared with asymptomatic patients (24.8 ± 5.1 kg/m(2) , P = .006). Additionally, the average BMI of patients with a high diuretic requirement (≥40 mg/day IV furosemide equivalent) was obese, at 32.15 ± 9.1 kg/m(2) , compared with 25.91 ± 7.3 kg/m(2) for those on no or lower doses of diuretics (P = .009). Eighteen of the 79 patients met an endpoint of death, hospice placement, or cardiac transplant by the study conclusion. Kaplan-Meier analysis from time of first appointment until recent follow-up revealed a significant association between time to combined endpoint and BMI class. Cox proportional hazard modeling with age adjustment yielded a hazard ratio of 3.2 (95% CI 1.096-9.379) for obesity upon first presentation to an adult CHD clinic.In patients with univentricular hearts and Fontan palliation, obesity is associated with symptomatic heart failure and mortality.

Limited evidence exists regarding the utility of genetic risk scores (GRS) in predicting recurrent cardiovascular events after acute coronary syndrome (ACS). We sought to determine whether a GRS would predict early recurrent cardiovascular events within 1 year of ACS.Participants admitted with acute coronary syndromes from the RISCA, PRAXY, and TRIUMPH cohorts, were genotyped for 30 single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD) or myocardial infarction (MI) in prior genome wide association studies. A 30 SNP CAD/MI GRS was constructed. The primary endpoint was defined as all-cause mortality, recurrent ACS or cardiac re-hospitalization within 1 year of ACS admission. Results across all cohorts for the 30 SNP CAD/MI GRS were pooled using a random-effects model. There were 1040 patients from the RISCA cohort, 691 patients from the PRAXY cohort, and 1772 patients from the TRIUMPH cohort included in the analysis and 389 occurrences of the primary endpoint of recurrent events at 1-year post-ACS. In unadjusted and fully adjusted analyses, a 30 SNP GRS was not significantly associated with recurrent events (HR per allele 0.97 (95%CI 0.91-1.03) for RISCA, HR 0.99 (95%CI 0.93-1.05) for PRAXY, 0.98 (95%CI 0.94-1.02) for TRIUMPH, and 0.98 (95%CI 0.95-1.01) for the pooled analysis). Addition of this GRS to the GRACE risk model did not significantly improve risk prediction.The 30 MI SNP GRS was not associated with recurrent events 1-year post ACS in pooled analyses across cohorts and did not improve risk discrimination or reclassification indices. Our results suggest that the genetic etiology of early events post-ACS may differ from later events.

Myeloperoxidase (MPO) is a circulating cardiovascular disease (CVD) biomarker used to estimate clinical risk and patient prognosis. Current enzyme-linked immunosorbent assays (ELISA) for MPO concentration are costly and time-intensive. Here we report a novel bioluminescence assay, designated MPO activity on a polymer surface (MAPS), for measuring MPO activity in human plasma samples using the bioluminescent substrate L-012. The method delivers a result in under an hour and is resistant to confounding effects from endogenous MPO inhibitors. In a pilot clinical study, we compared MAPS and two clinical ELISAs using 72 plasma samples from cardiac catheterization patients. Results from parallel MAPS and ELISAs were concordant within 2±11 μg l−1 MPO with similar uncertainty and reproducibility. Results between parallel MAPS and ELISA were in better agreement than those between independent ELISAs. MAPS may provide an inexpensive and rapid assay for determining MPO activity in plasma samples from patients with CVD or potentially other immune and inflammatory disorders., Levels of the enzyme myeloperoxidase in the blood are considered a biomarker for the severity of cardiovascular disease. Here the authors report a rapid and inexpensive method for measuring myeloperoxidase activity in human plasma by luminescence, after adsorption of the enzyme to a polymer surface.

The physiologic demands of pregnancy may either trigger or uncover ischemic heart disease (IHD) via largely unknown mechanisms, leading to an increased mortality compared with nonpregnant individuals. Risk factors for IHD in pregnancy are age, smoking, multiparity, and prior cardiac events. A multidisciplinary team at a referral center is key to coordinating medical or invasive management and inpatient observation. Etiologies may be revealed by experienced angiographers, and are predominantly spontaneous coronary artery dissection, followed by atherosclerotic disease and thrombus, while a significant percentage of women are found to have normal coronary arteries by angiogram. The management of these conditions is varied and, in general, conservative management is preferred with adequate coronary flow and stable hemodynamics. A woman with a history of IHD in pregnancy is at a substantial risk for further complications in future pregnancies and beyond; therefore, aggressive risk factor-reduction strategies and regular cardiology follow-up are imperative to decrease adverse events.

Background The combination of elevated glucose and free-fatty acids (FFA), prevalent in diabetes, has been suggested to be a major contributor to pancreatic β-cell death. This study examines the synergistic effects of glucose and FFA on β-cell apoptosis and the molecular mechanisms involved. Mouse insulinoma cells and primary islets were treated with palmitate at increasing glucose and effects on apoptosis, endoplasmic reticulum (ER) stress and insulin receptor substrate (IRS) signaling were examined. Principal Findings Increasing glucose (5–25 mM) with palmitate (400 µM) had synergistic effects on apoptosis. Jun NH2-terminal kinase (JNK) activation peaked at the lowest glucose concentration, in contrast to a progressive reduction in IRS2 protein and impairment of insulin receptor substrate signaling. A synergistic effect was observed on activation of ER stress markers, along with recruitment of SREBP1 to the nucleus. These findings were confirmed in primary islets. The above effects associated with an increase in glycogen synthase kinase 3β (Gsk3β) activity and were reversed along with apoptosis by an adenovirus expressing a kinase dead Gsk3β. Conclusions/Significance Glucose in the presence of FFA results in synergistic effects on ER stress, impaired insulin receptor substrate signaling and Gsk3β activation. The data support the importance of controlling both hyperglycemia and hyperlipidemia in the management of Type 2 diabetes, and identify pancreatic islet β-cell Gsk3β as a potential therapeutic target.

Despite treatment with agents that enhance β-cell function and insulin action, reduction in β-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3β (Gsk-3β). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3β to regulation of β-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/−) exhibit insulin resistance and a doubling of β-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3β (Gsk-3β+/−) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced β-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2−/−), like the Ir+/− mice, are insulin resistant, but develop profound β-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3β activity associated with a marked reduction of β-cell proliferation and increased apoptosis. Irs2−/− mice crossed with Gsk-3β+/− mice preserved β-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2−/− mice had increased cyclin-dependent kinase inhibitor p27kip1 that was limiting for β-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of β-cell mass in Gsk-3β+/−Irs2−/− mice was accompanied by suppressed p27kip1 levels and increased Pdx1 levels. To separate peripheral versus β-cell–specific effects of reduction of Gsk3β activity on preservation of β-cell mass, mice homozygous for a floxed Gsk-3β allele (Gsk-3F/F) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce β-cell–specific knockout of Gsk-3β (βGsk-3β−/−). Like Gsk-3β+/− mice, βGsk-3β−/− mice also prevented the diabetes of the Irs2−/− mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within β-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of β-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve β-cells and prevent diabetes onset., Author Summary Diabetes is often characterized by a failure of insulin production by pancreatic β-cells to properly regulate glucose homeostasis. Insulin resistance can lead to β-cell failure, and our studies have focused on elucidating the mechanisms involved in this postnatal failure. In this study, we evaluated a new, negatively regulated enzyme of the insulin signaling pathway, glycogen synthase kinase 3 (Gsk-3), specifically within insulin-producing pancreatic β-cells. When this enzyme is elevated, it can impair replication and increase cell death, resulting in loss of insulin-producing cells and diabetes. Gsk-3 is also known to regulate cell death and proliferation in neurons. We assessed the role of Gsk-3 on glucose homeostasis in two different mouse models of insulin resistance. We demonstrated that genetically reducing the levels of Gsk-3β in the insulin-resistant mouse improved glucose homeostasis. In another model in which severe insulin resistance is associated with destruction of β-cells, reducing Gsk-3β not only preserved β-cells by increasing proliferation and reducing cell death, but it also corrected diabetes. Controlling activity of Gsk-3 could lead to new hopes for maintaining or improving β-cell number and prevention of diabetes., The insulin signaling pathway negatively regulates glycogen synthase kinase 3. The current studies demonstrate that this enzyme is rate limiting for pancreatic β-cell replication and survival.

biventricular support (BVAD). This study examines the differences in outcomes in post-transplantation survival in patients with TAH or BVAD as BTT. Methods: Heart transplant patients listed in United Network of Organ Sharing (UNOS) from January 2005 to June 2013 (n= 14,707) were retrospectively investigated. Patients supported with either a TAH (n= 144) or BVAD (n= 330) before transplantation were evaluated. Post-transplantation Kaplan-Meier survival curves were examined. Cox regression model was used to study the hazard ratios for the association between TAH vs. BVAD support and post-transplant survival. Results: The median age of the study groups are 53±12 (TAH) and 51±13 (BVAD) years (range 18-74 years). There were more men, 89% vs 75%, in the TAH group (p< 0.0003) with greater BMIs, 26.9±4.7 vs 25.6±4.7, (p< 0.0001) compared to those with BVADs. The 30-day, one and two-year post-transplantation graft survival was 89.4%, 72.9%, and 61,8% respectively for patients with TAH support vs. 92.9% (p= 0.2), 84% (p= 0.03) and 79% (p= 0.01) for patients with BIVAD support. Cox regression model showed that pre-transplant creatinine (HR= 1.21, p= 0.008) is associated with a lower post-transplant survival. Conclusion: Although there has been a recent increase in the use of the TAH as BTT, BVAD support remains a viable option with potentially better posttransplant survival beyond one year.

terquartile range $185,045-$288,411) (p 0.00001, p 0.0001, respectively). Conclusions: CF-LVAD implant prior to need for inotropes is associated with shorter length of stay and lower direct cost. Evolution of implant criteria and timing is likely to have has a major impact on determining cost effectiveness of CF-LVAD. The conduct of a clinical trial evaluating the LVAD therapy in an earlier stage heart failure patient population may have a significant and favorable impact on the cost of health care delivery.

Coronary artery disease (CAD) is a complex, heritable disease. Genome-wide association studies (GWAS) defined 41 independent single-nucleotide polymorphisms (SNPs) associated with an increased risk of CAD, independent of clinical factors. We hypothesized that this genetic risk score would also be