Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart : prospects for molecular ventricular assistance.

BACKGROUND: Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human beta(2)AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. METHODS AND RESULTS: Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-betaGal) or the beta(2)AR (Adeno-beta(2)AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-beta(2)AR resulted in approximately 10-fold overexpression in a chamber-specific manner. Delivery of Adeno-betaGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of beta(2)ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. CONCLUSIONS: Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the beta(2)AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.

Colonizing the heart from the epicardial side.

The clinical use of stem cells, such as bone marrow-derived and, more recently, resident cardiac stem cells, offers great promise for treatment of myocardial infarction and heart failure. The epicardium-derived cells have also attracted attention for their angiogenic paracrine actions and ability to differentiate into cardiomyocytes and vascular cells when activated during cardiac injury. In a recent study, Chong and colleagues have described a distinct population of epicardium-derived mesenchymal stem cells that reside in a perivascular niche of the heart and have a broad multilineage potential. Exploring the therapeutic capacity of these cells will be an exciting future endeavor.

The controlled delivery of hydrogen sulfide for the preservation of heart tissue

Gemstone Team Organ Storage and Hibernation

Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish.

Heart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program.

A model of sequential heart and composite tissue allotransplant in rats.

BACKGROUND: Some of the 600,000 patients with solid organ allotransplants need reconstruction with a composite tissue allotransplant, such as the hand, abdominal wall, or face. The aim of this study was to develop a rat model for assessing the effects of a secondary composite tissue allotransplant on a primary heart allotransplant. METHODS: Hearts of Wistar Kyoto rats were harvested and transplanted heterotopically to the neck of recipient Fisher 344 rats. The anastomoses were performed between the donor brachiocephalic artery and the recipient left common carotid artery, and between the donor pulmonary artery and the recipient external jugular vein. Recipients received cyclosporine A for 10 days only. Heart rate was assessed noninvasively. The sequential composite tissue allotransplant consisted of a 3 x 3-cm abdominal musculocutaneous flap harvested from Lewis rats and transplanted to the abdomen of the heart allotransplant recipients. The abdominal flap vessels were connected to the femoral vessels. No further immunosuppression was administered following the composite tissue allotransplant. Ten days after composite tissue allotransplantation, rejection of the heart and abdominal flap was assessed histologically. RESULTS: The rat survival rate of the two-stage transplant surgery was 80 percent. The transplanted heart rate decreased from 150 +/- 22 beats per minute immediately after transplant to 83 +/- 12 beats per minute on day 20 (10 days after stopping immunosuppression). CONCLUSIONS: This sequential allotransplant model is technically demanding. It will facilitate investigation of the effects of a secondary composite tissue allotransplant following primary solid organ transplantation and could be useful in developing future immunotherapeutic strategies.

The Impact of Worsening Heart Failure in the United States.

In-hospital worsening heart failure represents a clinical scenario wherein a patient hospitalized for acute heart failure experiences a worsening of their condition, requiring escalation of therapy. Worsening heart failure is associated with worse in-hospital and postdischarge outcomes. Worsening heart failure is increasingly being used as an endpoint or combined endpoint in clinical trials, as it is unique to episodes of acute heart failure and captures an important event during the inpatient course. While prediction models have been developed to identify worsening heart failure, there are no known FDA-approved medications associated with decreased worsening heart failure. Continued study is warranted.

Thinking Outside the Box: Treating Acute Heart Failure Outside the Hospital to Improve Care and Reduce Admissions.

The management of acute heart failure is shifting toward treatment approaches outside of a traditional hospital setting. Many heart failure providers are now treating patients in less familiar health care settings, such as acute care clinics, emergency departments, and skilled nursing facilities. In this review we describe the current pressures driving change in the delivery of acute heart failure and summarize the evidence regarding treatments for acute heart failure outside of the inpatient setting. We also provide considerations for the design of future treatment strategies to be implemented in alternative care settings.

Ventricular conduction and long-term heart failure outcomes and mortality in African Americans: insights from the Jackson Heart Study.

BACKGROUND: QRS prolongation is associated with adverse outcomes in mostly white populations, but its clinical significance is not well established for other groups. We investigated the association between QRS duration and mortality in African Americans. METHODS AND RESULTS: We analyzed data from 5146 African Americans in the Jackson Heart Study stratified by QRS duration on baseline 12-lead ECG. We defined QRS prolongation as QRS≥100 ms. We assessed the association between QRS duration and all-cause mortality using Cox proportional hazards models and reported the cumulative incidence of heart failure hospitalization. We identified factors associated with the development of QRS prolongation in patients with normal baseline QRS. At baseline, 30% (n=1528) of participants had QRS prolongation. The cumulative incidences of mortality and heart failure hospitalization were greater with versus without baseline QRS prolongation: 12.6% (95% confidence interval [CI], 11.0-14.4) versus 7.1% (95% CI, 6.3-8.0) and 8.2% (95% CI, 6.9-9.7) versus 4.4% (95% CI, 3.7-5.1), respectively. After risk adjustment, QRS prolongation was associated with increased mortality (hazard ratio, 1.27; 95% CI, 1.03-1.56; P=0.02). There was a linear relationship between QRS duration and mortality (hazard ratio per 10 ms increase, 1.06; 95% CI, 1.01-1.12). Older age, male sex, prior myocardial infarction, lower ejection fraction, left ventricular hypertrophy, and left ventricular dilatation were associated with the development of QRS prolongation. CONCLUSIONS: QRS prolongation in African Americans was associated with increased mortality and heart failure hospitalization. Factors associated with developing QRS prolongation included age, male sex, prior myocardial infarction, and left ventricular structural abnormalities.

Identifying Barriers and Practical Solutions to Conducting Site-Based Research in North America: Exploring Acute Heart Failure Trials As a Case Study.

Although the prognosis of ambulatory heart failure (HF) has improved dramatically there have been few advances in the management of acute HF (AHF). Despite regional differences in patient characteristics, background therapy, and event rates, AHF clinical trial enrollment has transitioned from North America and Western Europe to Eastern Europe, South America, and Asia-Pacific where regulatory burden and cost of conducting research may be less prohibitive. It is unclear if the results of clinical trials conducted outside of North America are generalizable to US patient populations. This article uses AHF as a paradigm and identifies barriers and practical solutions to successfully conducting site-based research in North America.

Two Cases of Late Shone Syndrome With Pulmonary Hypertension: Heart-Lung Transplant or Valve Surgery?

Two cases of Shone syndrome with severe mitral and aortic valve problems and pulmonary hypertension were referred for heart-lung transplantation. Severely elevated pulmonary vascular resistance (PVR) was confirmed as was severe periprosthetic mitral and aortic regurgitation. Based on the severity of the valve lesions in both patients, surgery was decided upon and undertaken. Both experienced early pulmonary hypertensive crises, one more than the other, that gradually subsided, followed by excellent recovery and reversal of pulmonary hypertension and PVR. These cases illustrate Braunwald's concept that pulmonary hypertension secondary to left-sided valve disease is reversible.

Reducing the incidence of coronary heart disease

The incidence of coronary heart disease (CHD) has been significantly reduced by the introduction of the National Service Framework in 2000 but has not yet reached set targets. This article analyses the adverse effects of specific CHD risk factors to the cardiovascular system and proposes local and national strategies for further reduction in the incidence, morbidity and mortality of CHD. It provides an example of how nurses can use a health promotion programme to support patients in giving up smoking, a major contributing factor in CHD. The programme uses cognitive behaviour therapy to improve patients' uptake and adherence.

Art always at heart

The Art Workers Guild, brother body to the SPAB and once presided over by William Morris and his followers, is 125 years old this year. Alan Powers looks back over its history, and sheds light on the characters and common bonds between the two bodies – while present Brothers of the Guild are pictured at work by photographer Lara Platman for new book to mark the event.

'Bowing from the heart': an investigation into discourses of professionalism and the work of caring for students in further education

Since their incorporation in 1993, further education (FE) colleges in England have been responsible for their own staffing and, faced with funding constraints as well as recruitment and retention targets, some have introduced a new category of staff referred to here as 'learning support workers' (LSWs). Though their employment conditions and specific duties vary considerably, LSWs' work often includes providing individual care for students. In this small-scale study, using semi-structured interviews, the perceptions of some teachers and LSWs about the nature of their relationships with each other and with students are investigated. The study is set broadly in the context of debates about the impact of public sector reform on FE colleges and teachers. A discourse analysis approach is adopted in discussion of the data. The authors conclude that although they are differently positioned in relation to traditional discourses of professionalism, both teachers and LSWs are perceived to be carrying out what Hochschild termed 'emotional labour'. The contradictory nature of emotional labour is also highlighted. Some of the implications of employing a new group of workers in FE are discussed.