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Background Psychosocial evaluations are required for long-term mechanical circulatory support (MCS) candidates, no matter whether MCS will be destination therapy (DT) or a bridge to heart transplantation. Although guidelines specify psychosocial contraindications to MCS, there is no comprehensive examination of which psychosocial evaluation domains are most prognostic for clinical outcomes. We evaluated whether overall psychosocial risk, determined across all psychosocial domains, predicted outcomes, and which specific domains appeared responsible for any effects. Methods A single-site retrospective analysis was performed for adults receiving MCS between April 2004 and December 2017. Using an established rating system, we coded psychosocial evaluations to identify patients at low, moderate, or high overall risk. We similarly determined risk within each of 10 individual psychosocial domains. Multivariable analyses evaluated whether psychosocial risk predicted clinical decisions about MCS use (DT versus bridge), and postimplantation mortality, transplantation, rehospitalization, MCS pump exchange, and standardly defined adverse medical events (AEs). Results In 241 MCS recipients, greater overall psychosocial risk increased the likelihood of a DT decision (odds ratio, 1.76; P = 0.017); and postimplantation pump exchange and occurrence of AEs (hazard ratios [HRs] ≥ 1.25; P ≤ 0.042). The individual AEs most strongly predicted were cardiac arrhythmias and device malfunctions (HRs ≥ 1.39; P ≤ 0.032). The specific psychosocial domains predicting at least 1 study outcome were mental health problem severity, poorer medical adherence, and substance use (odds ratios and HRs ≥ 1.32; P ≤ 0.010). Conclusions The psychosocial evaluation predicts not only clinical decisions about MCS use (DT versus bridge) but important postimplantation outcomes. Strategies to address psychosocial risk factors before or soon after implantation may help to reduce postimplantation clinical risks.

Depression is often comorbid in patients with heart failure (HF) and is associated with worse clinical outcomes. However, depression generally goes unrecognized and untreated in this population.To determine whether a blended collaborative care program for treating both HF and depression can improve clinical outcomes more than collaborative care for HF only and physicians' usual care (UC).This 3-arm, single-blind, randomized effectiveness trial recruited 756 participants with HF with reduced left ventricular ejection fraction (45%) from 8 university-based and community hospitals in southwestern Pennsylvania between March 2014 and October 2017 and observed them until November 2018. Participants included 629 who screened positive for depression during hospitalization and 2 weeks postdischarge and 127 randomly sampled participants without depression to facilitate further comparisons. Key analyses were performed November 2018 to March 2019.Separate physician-supervised nurse teams provided either 12 months of collaborative care for HF and depression ("blended" care) or collaborative care for HF only (enhanced UC [eUC]).The primary outcome was mental health-related quality of life (mHRQOL) as measured by the Mental Component Summary of the 12-item Short Form Health Survey (MCS-12). Secondary outcomes included mood, physical function, HF pharmacotherapy use, rehospitalizations, and mortality.Of the 756 participants (mean [SD] age, 64.0 [13.0] years; 425 [56%] male), those with depression reported worse mHRQOL, mood, and physical function but were otherwise similar to those without depression (eg, mean left ventricular ejection fraction, 28%). At 12 months, blended care participants reported a 4.47-point improvement on the MCS-12 vs UC (95% CI, 1.65 to 7.28; P = .002), but similar scores as the eUC arm (1.12; 95% CI, -1.15 to 3.40; P = .33). Blended care participants also reported better mood than UC participants (Patient-Reported Outcomes Measurement Information System-Depression effect size, 0.47; 95% CI, 0.28 to 0.67) and eUC participants (0.24; 95% CI, 0.07 to 0.41), but physical function, HF pharmacotherapy use, rehospitalizations, and mortality were similar by both baseline depression and randomization status.In this randomized clinical trial of patients with HF and depression, telephone-delivered blended collaborative care produced modest improvements in mHRQOL, the primary outcome, on the MCS-12 vs UC but not eUC. Although blended care did not differentially affect rehospitalization and mortality, it improved mood better than eUC and UC and thus may enable organized health care systems to provide effective first-line depression care to medically complex patients.ClinicalTrials.gov Identifier: NCT02044211.

OBJECTIVE Despite numerous improvements in care, morbidity from heart failure (HF) has remained essentially unchanged in recent years. One potential reason is that depression, which is comorbid in approximately 40% of hospitalized HF patients and associated with adverse HF outcomes, often goes unrecognized and untreated. The Hopeful Heart Trial is the first study to evaluate whether a widely generalizable telephone-delivered collaborative care program for treating depression in HF patients improves clinical outcomes. METHODS The Hopeful Heart Trial aimed to enroll 750 patients with reduced ejection fraction (HFrEF) (ejection fraction ≤ 45%) including the following: (A) 625 patients who screened positive for depression both during their hospitalization (Patient Health Questionnaire [PHQ-2]) and two weeks following discharge (PHQ-9 ≥ 10); and (B) 125 non-depressed control patients (PHQ-2(-)/PHQ-9 < 5). We randomized depressed patients to either their primary care physician's "usual care" (UC) or to one of two nurse-delivered 12-month collaborative care programs for (a) depression and HFrEF ("blended") or (b) HrEFF alone (enhanced UC). Our co-primary hypotheses will test whether "blended" care can improve mental health-related quality of life versus UC and versus enhanced UC, respectively, on the Mental Component Summary of the Short-Form 12 Health Survey. Secondary hypotheses will evaluate the effectiveness of our interventions on mood, functional status, hospital readmissions, deaths, provision of evidence-based care for HFrEF, and treatment costs. RESULTS Not applicable. CONCLUSIONS The Hopeful Heart Trial will determine whether "blended" collaborative care for depression and HFrEF is more effective at improving patient-relevant outcomes than collaborative care for HFrEF alone or doctors' UC for HFrEF. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02044211.

Introduction: Patients admitted with decompensated heart failure (HF) are at risk for hospital readmission and poor quality of life. Remote monitoring and mobile health (mHealth) technologies can help prevent hospitalization for community-dwelling patients. We aimed to develop a HF mHealth application to enhance self-care after HF hospitalization. Hypothesis: We hypothesized that 1) a mHealth platform could be designed to increase HF self-care after hospital discharge for a population at high risk for HF readmission and 2) our tool would be user friendly and feasibly deployed. Methods: Intervention development included input from the following stakeholders: patients, clinicians, information technology developers, patient education experts, and mHealth researchers. We recruited 32 inpatient adults with HF and randomized them 1:1 to the mHealth program plus usual HF care or usual care only. Patients discharged to a nursing home, with end-stage HF (e.g. awaiting transplant/ventricular assist device or on palliative inotropes), or without a smart phone were excluded. Feasibility was determined by ease of deployment, duration of participant recruitment, and participant attrition. We measured program usability by how often the application was opened and used by patients. Results: We developed an educational HF mHealth patient self-care tool consisting of daily videos and self-assessments. Of 202 patients screened: 13 were excluded due to discharge to nursing home; 28 were excluded for end-stage HF; 9 were excluded because they did not have a smart phone. We enrolled 32 patients, 14 of which were randomized to receive the program. Mean age was 60 years (range 22-85). There were 53% male and 81% White. Four of 14 (28.6%) did not fully complete the 90-day program. All survey respondents expressed satisfaction with the intervention. Conclusions: We conducted a pilot study of a HF self-care mHealth tool for adults at risk for HF readmission and have determined it to be both feasible and acceptable. Our intervention, although a research prototype, may serve as a novel approach to reduce hospital admission and improve patient ability to manage HF as an outpatient.

Globally, acute heart failure (AHF) remains an ongoing public health issue with its prevalence and mortality increasing in the east and the west. Effective treatment strategies to stabilize AHF are important to alleviate clinical symptoms and to improve clinical outcomes. However, despite the progress in the management of stable and chronic heart failure, no single agent has been proven to play a definitive role in the management of AHF. As a consequence, contemporary treatment strategies for patients with AHF vary greatly by region. This manuscript reviews the medical treatment options for AHF, with an emphasis on the differences between the treatment strategies in the USA and Japan. This information would provide a framework for clinicians to evaluate and manage patients with AHF and highlight the remaining questions to improve clinical outcomes.

The criteria for being placed on the list of the International Society for Heart and Lung Transplantation for an orthotopic heart transplant mention nothing about patients with aortic dissection. Nor are there any guidelines pertaining to the patient with type B aortic dissection. Herein, we report the case of a patient with chronic type B aortic dissection for whom we successfully performed a left ventricular assist device implant followed by an orthotopic heart transplant.

Chest pain is a common presenting complaint faced by the rapid response team (RRT), and can herald a serious process such as acute coronary syndrome or aortic dissection, or be secondary to a minor muscle strain. A methodical approach to chest pain is necessary to avoid premature diagnostic closure. One of the most feared diagnoses is a myocardial infarction. Fortunately, there are well-established guidelines describing the necessary steps for treatment of both ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI). This chapter will address the differential for chest pain as well as established guidelines for treatment of acute coronary syndrome.

Globally, acute heart failure (AHF) remains an ongoing public health issue with its prevalence and mortality increasing in the east and the west. Effective treatment strategies to stabilize AHF are important to alleviate clinical symptoms and to improve clinical outcomes. However, despite the progress in the management of stable and chronic heart failure, no single agent has been proven to play a definitive role in the management of AHF. As a consequence, contemporary treatment strategies for patients with AHF vary greatly by region. This manuscript reviews the medical treatment options for AHF, with an emphasis on the differences between the treatment strategies in the USA and Japan. This information would provide a framework for clinicians to evaluate and manage patients with AHF and highlight the remaining questions to improve clinical outcomes.

Purpose A psychosocial evaluation is required for candidates for long-term mechanical circulatory support (MCS). Despite guidelines and recommendations for elements to be included in this evaluation, few data indicate whether evaluation findings are prognostic for adverse outcomes after MCS implantation. We examined this issue with respect to post-implant survival time, rehospitalization, and adverse medical events (AEs). Methods A single-site retrospective analysis was performed using prospectively collected data for all patients aged ≥18 receiving long-term MCS between 4/2004-12/2017. We coded pre-implant psychosocial evaluations with an established rating system (Psychosocial Assessment of Candidates for Transplantation, Modified for MCS; m-PACT). The m-PACT yields a Total score (calculated so that higher=less favorable; range=0-20) and scores for 10 components reflecting social support; mental health and substance use; ability to perform activities of daily living; and knowledge and adherence to current medical requirements. Competing risk models (competing risks: transplant, weaning from MCS) were estimated to determine associations of m-PACT Total and component scores with survival time on MCS, time to unscheduled rehospitalization, and time to any of 14 classes of AEs. Pre-implant demographic and clinical factors were controlled. Results In 238 MCS patients (M±SD age 56±13, 81% male, 83% white, 62% bridge to transplant, median time on MCS=256 days), survival time and time to rehospitalization were not significantly associated with m-PACT Total. However, for each 1-point m-PACT Total score increase, AE risk increased by 7% (hazard ratio, HR=1.07, CI: 1.01, 1.15, p=.028). The individual types of AEs most affected were cardiovascular dysfunction and device malfunctions. The m-PACT components accounting for the influence of m-PACT Total on AE risk were poorer medical adherence at the time of the evaluation (HR=1.74, CI: 1.14, 1.67, p=.001), and mental health problems (HR=1.20, CI: 1.02, 1.61, p=.035). Conclusion The psychosocial evaluation may provide prognostic information for post-implant outcomes. Strategies to address psychosocial risk factors either before implant or as soon as possible post-implant may help to reduce AE risk and thereby promote patient well-being during MCS.

Causative etiology of non-ischemic and stress-induced cardiomyopathy can be challenging, but is often useful to predict prognosis and facilitate decision making. A 35-year-old female presented with nausea, vomiting, dizziness, diarrhea and was noted to be cold and diaphoretic with elevated lactate

Heart transplantation in adults with congenital heart disease (CHD) has historically been associated with sub-optimal survival compared with other indications for transplantation. The purpose of this study was to evaluate survival outcomes after heart transplantation in a contemporary cohort of adults with CHD and to identify risk factors for mortality that may help guide recipient and donor selection.We performed a retrospective analysis of our adult heart transplant database, from January 2001 to February 2011, identifying 19 patients who underwent transplantation for CHD. These patients were compared with a control group of 428 patients who underwent transplantation for indications other than CHD. Kaplan-Meier survival analysis and Cox regression modeling were performed.The mean age for the CHD group was 39.4 ± 13 years vs 54.7 ± 12 years (p0.001). There was no significant difference in survival (CHD vs control) at 30 days (89% vs 92%, p = 0.5567), 1 year (84% vs 86%, p = 0.6976) or 5 years (70% vs 72%, p = 0.8478). The only significant predictor of death in the CHD group was donor organ ischemic time4 hours (HR 13.26, 95% CI 1.3 to 132.2, p = 0.028). There was no significant correlation with recipient age, history of failed Fontan surgery, pre-operative ventilator use, donor:recipient weight ratio0.8, donor:recipient CMV mismatch, model for end-stage liver disease (MELD) score or percent reactive antibody10%.In the modern era, with careful donor and recipient selection, adults with CHD have excellent early and mid-term survival after heart transplantation, rivaling that of recipients with other indications for transplantation.

ObjectivesThis study was conducted to test the hypothesis that cardiac micro-ribonucleic acid (miR) profiling in severe heart failure patients at the time of ventricular assist device (VAD) placement would differentiate those who remained VAD-dependent from those with subsequent left ventricular (LV) recovery.BackgroundThe relationship of myocardial miR expression to ventricular recovery is unknown.MethodsWe studied 28 patients with nonischemic cardiomyopathy requiring VAD support consisting of test and validation cohorts from 2 institutions: 14 with subsequent LV recovery and VAD removal and 14 clinically matched VAD-dependent patients. Apical core myocardium was studied for expression of 376 miRs by polymerase chain reaction (PCR) array and real-time-PCR methods. Samples from 7 nonfailing hearts were used in confirmatory studies.ResultsBy PCR array, 10 miRs were differentially expressed between LV recovery and VAD-dependent patients in the test cohort. The real-time PCR confirmed lower expression in LV recovery patients for 4 miRs (15b, −1.5-fold; 23a, −2.2-fold; 26a, −1.4-fold; and 195, −1.8-fold; all p < 0.04 vs. VAD dependent). The validation cohort similarly showed lower miRs expression in LV recovery patients (23a, −1.8-fold; and 195, −1.5-fold; both p < 0.03). Furthermore, miR 23a and 195 expression in nonfailing hearts was similar to LV recovery patients (both p < 0.04 vs. VAD dependent). The LV recovery patients also had significantly smaller cardiomyocytes by quantitative histology in both cohorts.ConclusionsLower cardiac expression of miRs 23a and 195 and smaller cardiomyocyte size at the time of VAD placement were associated with subsequent LV functional recovery. Differential expression of miRs at VAD placement may provide markers to assess recovery potential.

Background: The prevalence of adult congenital heart disease (ACHD) patients with heart failure is increasing. No guidelines exist for evaluation and listing for heart transplant (HT) in ACHD. We sought to review the outcomes of HT committee decisions [accepted and transplanted (T), accepted awaiting transplant (A), deferred (D), ineligible (I)]. Methods: This was a retrospective analysis performed on ACHD (≥ 18 yrs) referred for HT between 2000-2014. Data on demographics, CHD severity, NYHA class, imaging, exercise testing, catheterization and HT committee decision were recorded. Primary outcome was all-cause mortality. Analysis was completed to identify variables that were statistically different amongst groups. Results: Sixty-two ACHD were included in analysis, A (n= 17) I (n=14) T (n=22) D (n=9), NYHA class III-IV (98%), CHD of great complexity (74%). Median time to HT, after listing, was 3 mo. (mean 5.5). Survival was significantly lower in the group awaiting transplant compared to all other groups (pFig ). Among those who had not been transplanted, several variables were significantly different (p Conclusion: Waitlist mortality in the ACHD population is high. Given poor outcomes while on the waitlist, earlier listing may improve survival. Specific variables were statically different among patients not transplanted and there was a high mortality in those with PH. These may have contributed to the difference in survival among groups and may impact HT committees in the evaluation and listing for HT.

Background Because transthoracic echocardiography (TTE) has significant limitations in assessing changes consequent to myocardial infarction (MI) in mice, we studied two novel methods to characterize such infarcts. Methods Large MIs were produced by proximal left coronary artery ligation, and small MIs by distal left coronary artery ligation. Serum cardiac troponin I levels were measured 24 hours postoperatively. At 2 weeks, mice underwent transesophageal echocardiography (TEE) and TTE. Infarct sizes were determined histologically. Results Surviving mice were classified according to infarct size. TEE identified all histologically proven large infarcts, and 4 of 5 small infarcts. TTE identified 4 of 5 large infarcts, but only 1 of 5 small infarcts. TEE-derived fractional area change, but not TTE-estimated left ventricular fractional shortening, was significantly different among large, small, and sham infarcts. Cardiac troponin I showed excellent correlation with infarct size and mortality. Conclusions Cardiac troponin I was found to predict infarct size and mortality, whereas TEE proved superior to TTE in determining infarct size and/or myocardial function in a murine MI model. These tools should provide more accurate assessments in preclinical studies of ischemic cardiomyopathy.

Background— Significant variation exists within the endothelial nitric oxide synthase (NOS3) gene that may influence cardiovascular risk. The Asp 298 variant of NOS3 has a shorter half-life in endothelial cells. Given the importance of nitric oxide in the heart failure syndrome, we evaluated the effect of this variant on event-free survival in a population with systolic dysfunction. Methods and Results— Four hundred sixty-nine patients (72% male, 49% ischemic; mean age, 56±12 years) with systolic dysfunction (left ventricular ejection fraction ≤0.45) were enrolled in a study of Genetic Risk Assessment of Cardiac Events (GRACE). The polymorphism in exon 7 of NOS3, a G-T transition at position 894 that results in a Glu to Asp amino acid substitution for codon 298, was genotyped and subjects were followed prospectively to the end point of death or heart transplantation. Event-free survival was compared on the basis of the presence (group 1, n=266) or absence (group 2, n=203) of the Asp 298 variant. Event-free survival was significantly poorer in patients with the Asp 298 variant (percent event-free survival group 1 at 1/2/3 years=78/65/54; group 2=82/72/64, P =0.03). In subset analysis, the adverse impact of the Asp 298 variant was primarily in patients with nonischemic cardiomyopathy (group 1=82/73/63; group 2=87/79/71, P =0.03) and was not apparent among patients with ischemic heart disease (group 1=75/59/47; group 2=74/62/54, P =0.71). Conclusions— For patients with heart failure caused by systolic function, the Asp 298 variant of NOS3 is associated with poorer event-free survival, particularly in patients with nonischemic cardiomyopathy.

A 61-year-old female with a history of secundum atrial septal defect repair and hereditary hemorrhagic telangiectasia presented with epistaxis. She was found to have atypical atrial flutter with 2:1 atrioventricular conduction. Radiofrequency ablation was planned, but inferior vena cava interruption precluded right atrial (RA) access. The RA was then accessed through both subclavian veins, and activation mapping revealed a dense atriotomy scar in the posterolateral inferior RA. Wavefront propagation proceeded caudally through an area of slow conduction confined by the atriotomy scar. Atypical atrial flutter terminated during a second radiofrequency application to an isthmus confined by 2 regions of dense scar. The arrhythmia did not recur, although the patient later experienced typical atrial flutter and atrial fibrillation. High-output heart failure due to systemic arteriovenous shunt was confirmed by cardiac catheterization and improved markedly with bevacizumab therapy.

Tumor necrosis factor α (TNFα) may contribute to the pathologic process of congestive heart failure (CHF). TNFα signaling occurs through two receptors; TNFR1 (TNFRSF1A) and TNFRII (TNFRSF1B). In humans a single nucleotide polymorphism (rs1061622 in TNFRSF1B exon 6; T587G) encodes two different amino acids (M196R) in the transmembrane region . The 587G allele is associated with greater severity and/or prevalence of some inflammatory diseases, but its role in CHF in unknown. This study sought to test the hypothesis that the 587G allele is associated with a worse outcome or more severe phenotype in CHF. Peripheral blood DNA was isolated and genotyped from 379 heart failure patients enrolled in a genetic outcome study (GRACE); (44.7% ischemic, 70.4% male, 8.5% black race, age 55.6+/−11.7 yr (SD), LVEF 0.245+/−8.3%, NYHA 2.53+/−0.64). Genotyping was performed by PCR-RFLP. Cardiac function was assessed from medical records at study entry. The distribution of genotypes in this population was 54% T/T, 38.4% G/T, and 7.7% G/G. Mean LV ejection fraction (T/T 24.4+/−8.2, T/G 25.0+/−8.4, G/G 23.3+/−8.6, n=352, p=ns) and LV end-diastolic dimensions (T/T 6.57+/−0.93, T/G 6.53+/−1.0, G/G 6.57+/−0.78, n=211, p=ns) were comparable in all groups. Transplant-free survival (median 23 months (range 1–62 months) did not vary by genotype (p=0.95). A lack of effect (p=0.74) on transplant-free survival was also observed in a subset of patients with ischemic heart failure (n=169). The TNFRSF1B 587G allele is not associated with the severity of heart failure phenotype or clinical outcomes in patients with chronic CHF.

Background: The expression of cardiac sodium/glucose cotransporter 1 (SGLT1) is up-regulated in ischemic heart disease. However, the regulation and the biological role of SGLT1 activity in cardiomyocytes are unclear. Hypothesis: We hypothesize that SGLT1 inhibition during ischemia-reperfusion (IR) will lead to worsening cardiac function and recovery. In addition we hypothesize that SGLT1 expression is upregulated by increased AMPK activity in ischemia. Methods: Transgenic mice with cardiac-specific RNAi knockdown of SGLT1 (TG SGLT1-KD ) were subjected to ex vivo IR (n > 3/group) using a Langendorff hanging heart preparation with 15 min of no-flow ischemia and 20 min of reperfusion while undergoing hemodynamic monitoring. FVB strain wild-type 8-12 week-old male mice (n > 3/group) were administered either the SGLT1 inhibitor phlorizin (400 mg/kg IP) or vehicle and subjected to in vivo ischemia for 30 min by ligation of the left anterior descending (LAD) coronary artery. Hearts were harvested 48 hours later. In vitro studies were conducted in HL-1 cardiomyocytes subjected to 1 h of simulated ischemia with 1 mM NaCN. HL-1 cells were also treated with 1 mM AICAR, an AMPK activator, for 16 hours and SGLT1 expression was measured. Results: In ex vivo IR studies, there was an impairment in the early recovery of double product in the TG SGLT1-KD mice compared to control mice (37% vs 92% at 1 min into reperfusion, P < 0.05). In in vivo IR studies, phlorizin led to a marked increase in oxidative stress documented by cardiac malondialdehyde (MDA) (control 1.00±0.00; IR 1.55±0.35; IR + phlorizin 16.15±0.40, P P P Conclusion: SGLT1 expression increases when cardiomyocytes are subjected to ischemia, an effect that may be mediated by AMPK. Inhibition of SGLT1 leads to impaired myocardial recovery from ischemia.

Hypothesis: Adenoviral-mediated (AdV-T2) overexpression of TIMP-2 would blunt ventricular remodeling and improve survival in a murine model of chronic ischemic injury. Methods: Male mice (n = 124) aged 10–14 weeks underwent either (1) left coronary artery ligation to induce myocardial infarction (MI group, n = 36), (2) myocardial injection of 6 × 1010 viral particles of AdV-T2 immediately post-MI (MI + T2 group, n = 30), (3) myocardial injection of 6 × 1010 viral particles of a control adenovirus (MI + Ct, n = 38), or 4) received no intervention (controls, n = 20). On post-MI day 7, surviving mice (n = 79) underwent echocardiographic, immunohistochemical, and biochemical analysis. Results: In infarcted animals, the MI + T2 group demonstrated improved survival (p < 0.02), better preservation of developed pressure and ventricular diameter (p < 0.04), and the lowest expression and activity of MMP-2 and MMP-9 (p < 0.04) compared with MI and MI + Ct groups. All infarcted hearts displayed significantly increased inflammatory cell infiltration (p < 0.04 vs. control, MI, or MI + T2), with infiltration highest in the MI + Ct group and lowest in the MI + T2 group (p < 0.04). Conclusions: Adenoviral mediated myocardial delivery of the TIMP-2 gene improves post-MI survival and limits adverse remodeling in a murine model of MI. Clin Trans Sci 2011; Volume 4: 24–31

Nitrated fatty acids (NO(2)-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO(2)) and nitro-linoleic acid (LNO(2)) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO(2) on I/R injury was evaluated.In C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO(2) and LNO(2) formation was observed after 30 min of reperfusion, whereas no NO(2)-FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion. Exogenous administration of 20 nmol/g body weight OA-NO(2) during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice. Administration of OA-NO(2) inhibited activation of the p65 subunit of nuclear factor kappaB (NFkappaB) in I/R tissue. Experiments using the NFkappaB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO(2) was in part mediated by inhibition of NFkappaB. OA-NO(2) inhibition of NFkappaB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis.This study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO(2) in myocardial I/R injury.

Dominant mutations in the gamma2 regulatory subunit of AMP-activated protein kinase (AMPK), encoded by the gene PRKAG2, cause glycogen storage cardiomyopathy. We sought to elucidate the effect of the Thr400Asn (T400N) human mutation in a transgenic mouse (TGT400N) on AMPK activity, and its ability to protect the heart against ischemia-reperfusion injury. TGT400N hearts had markedly vacuolated myocytes, excessive accumulation of glycogen, hypertrophy, and preexcitation. Early activation of myocardial AMPK, followed by depression, and then recovery to wild-type levels was observed. AMPK activity correlated inversely with glycogen content. Partial rescue of the phenotype was observed when TGT400N mice were crossbred with TGalpha2DN mice, which overexpress a dominant negative mutant of the AMPK alpha2 catalytic subunit. TGT400N hearts had greater infarct sizes and apoptosis when subjected to ischemia-reperfusion. Increased AMPK activity is responsible for glycogen storage cardiomyopathy. Despite high glycogen content, the TGT400N heart is not protected against ischemia-reperfusion injury.

Purpose INTERMACS data show that select AE’s lead to higher mortality during VAD support. However, the extent to which these AE’s experienced early (within 60 days) after VAD implant effect long-term survival after this time period is not known for those with a CF-VAD. Methods and Materials We analyzed prospectively collected data from a single-center database on adults implanted with a CF-VAD (2004-2011) who survived beyond 60 days. 14 different classes of AE’s as defined by INTERMACS were assessed during the first 60 days post-implant. For each AE, 1-year survival was compared for those with and without the AE using Kaplan-Meier analysis. Any class of AEs at least marginally associated (p Results In 91 patients, the mean age was 56 years, 81% were male, 82% were white, and 65% were bridge to transplant. The occurrence of right ventricular failure (RVF), renal, neurologic, and respiratory events in the first 60 days of support were associated with significantly increased mortality at 12 months (p figure 1 ] Conclusions Of the 14 major AE’s experienced early after CF-VAD implantation, only RVF, renal, neurologic, and respiratory events had significant long-term effects on mortality that persisted beyond the initial event. The only early AE that was an independent predictor of poor late outcome was RVF.

The aim of the present study was to investigate the importance of tumor necrosis factor (TNF)-α receptor-1 (TNFR1)-mediated pathways in a murine model of myocardial infarction and remodeling. One hundred and ninety-four wild-type (WT) and TNFR1 gene-deleted (TNFR1KO) mice underwent left coronary artery ligation to induce myocardial infarction. On days 1, 3, 7, and 42, mice underwent transesophageal echocardiography. Hearts were weighed, and the left ventricle (LV) was assayed for matrix metalloproteinase (MMP)-2 and -9 activity and for tissue inhibitor of MMP (TIMP)-1 and -2 expression. Deletion of the TNFR1 gene substantially improved survival because no deaths were observed in TNFR1KO mice versus 56.4% and 18.2% in WT males and females, respectively ( P < 0.002). At 42 days, LV remodeling, assessed by LV function (fractional area change of 31.9 ± 7.9%, 32.2 ± 7.7%, and 21.6 ± 7.1% in TNFR1KO males, TNFR1KO females, and WT females, respectively, P < 0.04), and hypertrophy (heart weight-to-body weight ratios of 5.435 ± 0.986, 5.485 ± 0.677, and 6.726 ± 0.704 mg/g, P < 0.04) were ameliorated in TNFR1KO mice. MMP-9 activity was highest at 3 days postinfarction and was highest in WT males (1.9 ± 0.4 4, 3.6 ± 0.24, 1.15 ± 0.28, and 1.3 ± 1.2 ng/100 μg protein, respectively, in TNFR1KO males, WT males, TNFR1KO females, and WT females, respectively, P < 0.002), whereas at 3 days TIMP-1 mRNA fold upregulation compared with type- and sex-matched controls was lowest in WT males (138.32 ± 13.05, 46.74 ± 5.43, 186.09 ± 28.07, and 101.76 ± 22.48, respectively, P < 0.002). MMP-2 and TIMP-2 increased similarly in all infarcted groups. These findings suggest that the benefits of TNFR1 ablation might be attributable at least in part to the attenuation of cytokine-mediated imbalances in MMP-TIMP activity.

Caveolins are structural protein components of caveolar membrane domains. Caveolin-3, a muscle-specific member of the caveolin family, is expressed in skeletal muscle tissue and in the heart. The multiple roles that caveolin-3 plays in cellular physiology are becoming more apparent. We have shown that lack of caveolin-3 expression in skeletal muscle resembles limb-girdle muscular dystrophy-1C. In contrast, we have demonstrated that overexpression of caveolin-3 in skeletal muscle tissue promotes defects similar to those seen in Duchenne muscular dystrophy (DMD). Thus, a tight regulation of caveolin-3 expression is fundamental for normal muscle functions. Since caveolin-3 is also endogenously expressed in cardiac myocytes, and cardiomyopathies are observed in DMD patients, we looked at the effects of overexpression of caveolin-3 on cardiac structure and function by characterizing caveolin-3 transgenic mice. Our results indicate that overexpression of caveolin-3 causes severe cardiac tissue degeneration, fibrosis and a reduction in cardiac functions. We also show that dystrophin and its associated glycoproteins are down-regulated in caveolin-3 transgenic heart. In addition, we demonstrate that the activity of nitric oxide synthase (NOS) is down-regulated by high levels of caveolin-3 in the heart. Taken together, these results indicate that overexpression of caveolin-3 is sufficient to induce severe cardiomyopathy. In addition, these findings suggest that caveolin-3 transgenic mice may represent a valid mouse model for studying the molecular mechanisms underlying cardiomyopathies associated with Duchenne muscular dystrophy.

In summary, over a decade of investigation has demonstrated the pathophysiologic importance of TNF in the development and progression of cardiac dilatation and heart failure. Although the signaling pathways that regulate the cardiac production of TNF have not yet been identified and the potential benefits of TNF expression to the heart are not understood, the benefits of anticytokine therapy in animal models is marked. Unfortunately, these salutary effects in the laboratory have not transitioned to the bedside. To accomplish the translational portion of the cytokine story, we must identify the point in time during the transition from compensated to decompensated heart failure in which TNF is expressed. In addition, we must better understand the role that other down-stream and non-TNF-dependent cytokines play in the development of heart failure. Not all patients are the same; therefore, we must pursue clinical trials that will allow us to elucidate the optimal degree of TNF inhibition, identify the patients who are most likely to respond to TNF inhibition, and determine what the true, long-term effects of TNF inhibition may be. Finally, we must recognize that inflammatory activities can exist in tissues and organs in the absence of TNF. Thus, anticytokine strategies alone might not be effective in ameliorating the signs and symptoms of heart failure. It is hoped that the failure of recent studies to demonstrate salutary benefits in patients with class II to IV heart failure will not diminish enthusiasm for the long-term potential of anticytokine therapy.

BACKGROUND—Severe pulmonary hypertension (PH) in heart failure (HF) is a risk factor for adverse outcomes after heart transplantation (HTx). Left ventricular assist devices (LVADs) improve pulmonary hemodynamics, but our understanding of the degree of improvement and the effect on outcomes is still evolving. METHODS—We reviewed invasive pulmonary hemodynamics from 58 consecutive patients receiving LVAD support as a bridge to HTx from 1996 to 2003. The primary outcome was change in baseline transpulmonary gradient (TPG) during LVAD support and after HTx/recovery. The secondary outcome was post-HTx survival. RESULTS—All patients (age, 49 ± 14 years, 79% male, 40% ischemic) received a pulsatile LVAD (median support, 97 days; interquartile range [IQR], 31–222). Hemodynamic measurements were obtained at baseline (median, 1 day; IQR, 1–3), during early (median, 1 day; IQR, 0–4) and late (median, 75 days; IQR, 24–186) LVAD support, and after HTx/recovery (median, 28 days; IQR,17–40). Improvement in TPG occurred throughout LVAD support and was sustained after HTx/recovery. Levels of TPG reductions in patients with a baseline TPG in the highest quartile (14.1–26.0 mm Hg) were 8.6 ± 3.5 vs 6.5 ± 3.1 mm Hg in the lowest quartile (2.0 –7.7 mm Hg) during LVAD support (p = 0.102), with 90% vs 100% 30-day post-HTx survival (P = 0.113). CONCLUSION—Pulmonary hemodynamics and post-HTx survival were similar after pulsatile LVAD support in patients with and without pre-implant PH. LVAD support may be a useful strategy to reverse PH in carefully selected patients, thus improving candidacy for HTx. © 2010 International Society for Heart and Lung Transplantation. All rights reserved. Reprint requests: Marc A. Simon, MD, FACC, Assistant Professor of Medicine, Cardiovascular Institute, University of Pittsburgh, Scaife Hall S554, 200 Lothrop St, Pittsburgh, PA 15213. Telephone: 412-647-1174. Fax: 412-647-3913. simonma@upmc.edu. Disclosure statement None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. NIH Public Access Author Manuscript J Heart Lung Transplant. Author manuscript; available in PMC 2011 March 29. Published in final edited form as: J Heart Lung Transplant. 2010 February ; 29(2): 201–208. doi:10.1016/j.healun.2009.09.013. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript

Pump thrombosis requiring device exchange is a dreaded complication after implantation of a left ventricular assist device (LVAD). Sub-optimal inflow cannula (IC) positioning at the time of implant or changes in IC position due to weight gain or ventricular remodeling may lead to non-laminar flow.