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.

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.

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.

Influence of progressive renal dysfunction in chronic heart failure

Chronic heart failure (CHF) is often associated with impaired renal function due to hypoperfusion. Such patients are very sensitive to changes in renal perfusion pressure, and may develop acute tubular necrosis if the pressure falls too far. The situation is complicated by the use of diuretics, ACE inhibitors and spironolactone, all of which may affect renal function and potassium balance. Chronic renal failure (CRF) may also be associated with fluid overload. Anaemia and hypertension in CRF contribute to the development of left ventricular hypertrophy (LVH), which carries a poor prognosis, so correction of these factors is important.

Obesity associated severe asthma represents a distinct clinical phenotype - Analysis of the British Thoracic Society Difficult Asthma Registry patient cohort according to body mass index

BACKGROUND: Obesity has emerged as a risk factor for the development of asthma and it may also influence asthma control and airways inflammation. However, the role of obesity in severe asthma remains unclear. OBJECTIVE: To explore the association between obesity (defined by BMI) and severe asthma. METHODS: Data from the National Registry for dedicated UK Difficult Asthma Services were used to compare patient demographics, disease characteristics and healthcare utilisation between three body mass index (BMI) categories (normal weight: 18.5 -24.99, overweight: 25 -29.99, obese: =30) in a well characterised group of severe asthmatic adults. RESULTS: The study population consisted of 666 severe asthmatics with a median BMI of 29.8 (interquartile range 22.5 -34.0). The obese group exhibited greater asthma medication requirements in terms of maintenance corticosteroid therapy (48.9% versus 40.4% and 34.5% in the overweight and normal weight groups, respectively), steroid burst therapy and short-acting ß2-agonist (SABA) use per day. Significant differences were seen with gastro-oesophageal reflux disease (GORD) (53.9% versus 48.1% and 39.7% in the overweight and normal weight groups, respectively) and proton pump inhibitor (PPI) use. Bone density scores were higher in the obese group, whilst pulmonary function testing revealed a reduced FVC and raised Kco. Serum IgE levels decreased with increasing BMI and the obese group were more likely to report eczema, but less likely to have a history of nasal polyps. CONCLUSIONS: Severe asthmatics display particular characteristics according to BMI that support the view that obesity associated severe asthma may represent a distinct clinical phenotype.1Royal Brompton Hospital, London, UK;2Department of Computing, Imperial College, UK3Airways Disease, National Heart & Lung Institute, Imperial College, UK;4Centre for infection and immunity, Queen's University of Belfast, UK;5University of Leicester, UK;6The University of Manchester and University Hospital of South Manchester, UK;7Birmingham Heartlands Hospital, University of Birmingham, UK;8Gartnavel General Hospital, University of Glasgow, UK;9Glasgow Royal Infirmary, Glasgow, UKCorrespondence: Dr Andrew N. Menzies-Gow, Royal Brompton Hospital, Fulham Road, London SW3 6HP.

Unintended cardiac irradiation during left-sided breast cancer radiotherapy

Objective: Cardiac irradiation during left-sided breast radiotherapy may lead to
deleterious cardiac side effects. Using image guided radiotherapy, it is possible
to exclude the heart from treatment fields and monitor reproducibility of virtual simulation (VS) fields at treatment delivery using electronic portal imaging (EPI). Retrospectively, we evaluate the incidence of cardiac irradiation at VS and subsequent unintended cardiac irradiation during treatment.

Methods: Patients receiving left-sided radiotherapy to the breast or chest wall,
treated with a glancing photon field technique during a four-month period, were
included. VS images and EPIs during radiotherapy delivery were visually assessed.
The presence of any portion of the heart within the treatment field at VS or during treatment was recorded. Central lung distance and maximum heart distance were recorded.

Results: Of 128 patients, 45 (35.1%) had any portion of the heart within the
planned treatment field. Of these, inclusion of the heart was clinically unavoidable in 25 (55.6%). Of those with no heart included in the treatment fields at VS, 41 (49.4%) had presence of the heart as assessed on EPI during treatment.

Conclusion: Unintended cardiac irradiation during left-sided breast radiotherapy treatment occurs in a sizeable proportion of patients.

Advances in knowledge: Despite the use of three-dimensional computed tomography simulation and cardiac shielding, sizeable proportions of patients receiving left-sided breast cancer radiotherapy have unintended cardiac irradiation.

Volumetric modulated arc therapy and breath-hold in image-guided locoregional left-sided breast irradiation

PURPOSE: To investigate the effects of using volumetric modulated arc therapy (VMAT) and/or voluntary moderate deep inspiration breath-hold (vmDIBH) in the radiation therapy (RT) of left-sided breast cancer including the regional lymph nodes.

MATERIALS AND METHODS: For 13 patients, four treatment combinations were compared; 3D-conformal RT (i.e., forward IMRT) in free-breathing 3D-CRT(FB), 3D-CRT(vmDIBH), 2 partial arcs VMAT(FB), and VMAT(vmDIBH). Prescribed dose was 42.56 Gy in 16 fractions. For 10 additional patients, 3D-CRT and VMAT in vmDIBH only were also compared.

RESULTS: Dose conformity, PTV coverage, ipsilateral and total lung doses were significantly better for VMAT plans compared to 3D-CRT. Mean heart dose (D(mean,heart)) reduction in 3D-CRT(vmDIBH) was between 0.9 and 8.6 Gy, depending on initial D(mean,heart) (in 3D-CRT(FB) plans). VMAT(vmDIBH) reduced the D(mean,heart) further when D(mean,heart) was still >3.2 Gy in 3D-CRT(vmDIBH). Mean contralateral breast dose was higher for VMAT plans (2.7 Gy) compared to 3DCRT plans (0.7 Gy).

CONCLUSIONS: VMAT and 3D-CRT(vmDIBH) significantly reduced heart dose for patients treated with locoregional RT of left-sided breast cancer. When Dmean,heart exceeded 3.2 Gy in 3D-CRT(vmDIBH) plans, VMAT(vmDIBH) resulted in a cumulative heart dose reduction. VMAT also provided better target coverage and reduced ipsilateral lung dose, at the expense of a small increase in the dose to the contralateral breast.

The heart of a dragon: 3D anatomical reconstruction of the 'scaly-foot gastropod' (Mollusca: Gastropoda: Neomphalina) reveals its extraordinary circulatory system

Introduction: The 'scaly-foot gastropod' (Chrysomallon squamiferum Chen et al., 2015) from deep-sea hydrothermal vent ecosystems of the Indian Ocean is an active mobile gastropod occurring in locally high densities, and it is distinctive for the dermal scales covering the exterior surface of its foot. These iron-sulfide coated sclerites, and its nutritional dependence on endosymbiotic bacteria, are both noted as adaptations to the extreme environment in the flow of hydrogen sulfide. We present evidence for other adaptations of the 'scaly-foot gastropod' to life in an extreme environment, investigated through dissection and 3D tomographic reconstruction of the internal anatomy.

Results: Our anatomical investigations of juvenile and adult specimens reveal a large unganglionated nervous system, a simple and reduced digestive system, and that the animal is a simultaneous hermaphrodite. We show that Chrysomallon squamiferum relies on endosymbiotic bacteria throughout post-larval life. Of particular interest is the circulatory system: Chrysomallon has a very large ctenidium supported by extensive blood sinuses filled with haemocoel. The ctenidium provides oxygen for the host but the circulatory system is enlarged beyond the scope of other similar vent gastropods. At the posterior of the ctenidium is a remarkably large and well-developed heart. Based on the volume of the auricle and ventricle, the heart complex represents approximately 4 % of the body volume. This proportionally giant heart primarily sucks blood through the ctenidium and supplies the highly vascularised oesophageal gland. Thus we infer the elaborate cardiovascular system most likely evolved to oxygenate the endosymbionts in an oxygen poor environment and/or to supply hydrogen sulfide to the endosymbionts.

Conclusions: This study exemplifies how understanding the autecology of an organism can be enhanced by detailed investigation of internal anatomy. This gastropod is a large and active species that is abundant in its hydrothermal vent field ecosystem. Yet all of its remarkable features-protective dermal sclerites, circulatory system, high fecundity-can be viewed as adaptations beneficial to its endosymbiont microbes. We interpret these results to show that, as a result of specialisation to resolve energetic needs in an extreme chemosynthetic environment, this dramatic dragon-like species has become a carrying vessel for its bacteria.

Total eclipse of the heart: the AM CVn Gaia14aae/ASSASN-14cn

We report the discovery and characterization of a deeply eclipsing AM CVn-system, Gaia14aae (=ASSASN-14cn). Gaia14aae was identified independently by the All-Sky Automated Survey for Supernovae (ASAS-SN; Shappee et al.) and by the Gaia Science Alerts project, during two separate outbursts. A third outburst is seen in archival Pan-STARRS-1 (PS1; Schlafly et al.; Tonry et al.; Magnier et al.) and ASAS-SN data. Spectroscopy reveals a hot, hydrogen-deficient spectrum with clear double-peaked emission lines, consistent with an accreting double-degenerate classification. We use follow-up photometry to constrain the orbital parameters of the system. We find an orbital period of 49.71 min, which places Gaia14aae at the long period extremum of the outbursting AM CVn period distribution. Gaia14aae is dominated by the light from its accreting white dwarf (WD). Assuming an orbital inclination of 90° for the binary system, the contact phases of the WD lead to lower limits of 0.78 and 0.015 M⊙ on the masses of the accretor and donor, respectively, and a lower limit on the mass ratio of 0.019. Gaia14aae is only the third eclipsing AM CVn star known, and the first in which the WD is totally eclipsed. Using a helium WD model, we estimate the accretor's effective temperature to be 12 900 ± 200 K. The three outburst events occurred within four months of each other, while no other outburst activity is seen in the previous 8 yr of Catalina Real-time Transient Survey (CRTS; Drake et al.), Pan-STARRS-1 and ASAS-SN data. This suggests that these events might be rebrightenings of the first outburst rather than individual events.

Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: the Global Rheumatic Heart Disease Registry (the REMEDY study)

AIMS: Rheumatic heart disease (RHD) accounts for over a million premature deaths annually; however, there is little contemporary information on presentation, complications, and treatment.

METHODS AND RESULTS: This prospective registry enrolled 3343 patients (median age 28 years, 66.2% female) presenting with RHD at 25 hospitals in 12 African countries, India, and Yemen between January 2010 and November 2012. The majority (63.9%) had moderate-to-severe multivalvular disease complicated by congestive heart failure (33.4%), pulmonary hypertension (28.8%), atrial fibrillation (AF) (21.8%), stroke (7.1%), infective endocarditis (4%), and major bleeding (2.7%). One-quarter of adults and 5.3% of children had decreased left ventricular (LV) systolic function; 23% of adults and 14.1% of children had dilated LVs. Fifty-five percent (n = 1761) of patients were on secondary antibiotic prophylaxis. Oral anti-coagulants were prescribed in 69.5% (n = 946) of patients with mechanical valves (n = 501), AF (n = 397), and high-risk mitral stenosis in sinus rhythm (n = 48). However, only 28.3% (n = 269) had a therapeutic international normalized ratio. Among 1825 women of childbearing age (12-51 years), only 3.6% (n = 65) were on contraception. The utilization of valvuloplasty and valve surgery was higher in upper-middle compared with lower-income countries.

CONCLUSION: Rheumatic heart disease patients were young, predominantly female, and had high prevalence of major cardiovascular complications. There is suboptimal utilization of secondary antibiotic prophylaxis, oral anti-coagulation, and contraception, and variations in the use of percutaneous and surgical interventions by country income level.

Respiratory and non-respiratory sinus arrhythmia: implications for heart rate variability

The quantity of blood arriving at the left side of the heart oscillates throughout the breathing cycle due to the mechanics of breathing. Neurally regulated fluctuations in the length of the heart period act to dampen oscillations of the left ventricular stroke volume entering the aorta. We have reported that stroke volume oscillations but not spectral frequency variability stroke volume measures can be used to estimate the breathing frequency. This study investigated with the same recordings whether heart period oscillations or spectral heart rate variability measures could function as estimators of breathing frequency. Continuous 270 s cardiovascular recordings were obtained from 22 healthy adult volunteers in the supine and upright postures. Breathing was recorded simultaneously. Breathing frequency and heart period oscillation frequency were calculated manually, while heart rate variability spectral maximums were obtained using heart rate variability software. These estimates were compared to the breathing frequency using the Bland–Altman agreement procedure. Estimates were required to be \±10% (95% levels of agreement). The 95% levels of agreement measures for the heart period oscillation frequency (supine: -27.7 to 52.0%, upright: -37.8 to 45.9%) and the heart rate variability spectral maximum estimates (supine: -48.7 to 26.5% and -56.4 to 62.7%, upright: -37.8 to 39.3%) exceeded 10%. Multiple heart period oscillations were observed to occur during breathing cycles. Both respiratory and non-respiratory sinus arrhythmia was observed amongst healthy adults. This observation at least partly explains why heart period parameters and heart rate variability parameters are not reliable estimators of breathing frequency. In determining the validity of spectral heart rate variability measurements we suggest that it is the position of the spectral peaks and not the breathing

Time to Left Ventricular Reverse Remodeling after Cardiac Resynchronization Therapy: Better Late than Never

INTRODUCTION: Left ventricular reverse remodeling (LVRR), defined as reduction of end-diastolic and end-systolic dimensions and improvement of ejection fraction, is associated with the prognostic implications of cardiac resynchronization therapy (CRT). The time course of LVRR remains poorly characterized. Nevertheless, it has been suggested that it occurs ≤6 months after CRT. OBJECTIVE: To characterize the long-term echocardiographic and clinical evolution of patients with LVRR occurring >6 months after CRT and to identify predictors of a delayed LVRR response. METHODS: A total of 127 consecutive patients after successful CRT implantation were divided into three groups according to LVRR response: Group A, 19 patients (15%) with LVRR after >6 months (late LVRR); Group B, 58 patients (46%) with LVRR before 6 months (early LVRR); and Group C, 50 patients (39%) without LVRR during follow-up (no LVRR). RESULTS: The late LVRR group was older, more often had ischemic etiology and fewer patients were in NYHA class ≤II. Overall, group A presented LVRR between group B and C. This was also the case with the percentage of clinical response (68.4% vs. 94.8% vs. 38.3%, respectively, p<0.001), and hospital readmissions due to decompensated heart failure (31.6% vs. 12.1% vs. 57.1%, respectively, p<0.001). Ischemic etiology (OR 0.044; p=0.013) and NYHA functional class

Extracorporeal membrane oxygenation support after heart explantation: a proposal on how to deal with hyperacute rejection of heart transplant

Purpose: In extreme situations, such as hyperacute rejection of heart transplant or major bleeding per-operating complications, an urgent heart explantation might be the only means of survival. The aim of this experimental study was to improve the surgical technique and the hemodynamics of an Extracorporeal Membrane Oxygenation (ECMO) support through a peripheral vascular access in an acardia model. Methods: An ECMO support was established in 7 bovine experiments (59±6.1 kg) by the transjugular insertion to the caval axis of a self-expanded cannula, with return through a carotid artery. After baseline measurements of pump flow and arterial and central venous pressure, ventricular fibrillation was induced (B), the great arteries were clamped, the heart was excised and right and left atria remnants, containing the pulmonary veins, were sutured together leaving an atrial septal defect (ASD) over the cannula in the caval axis. Measurements were taken with the pulmonary artery (PA) clamped (C) and anastomosed with the caval axis (D). Regular arterial and central venous blood gases tests were performed. The ANOVA test for repeated measures was used to test the null hypothesis and a Bonferroni t method for assessing the significance in the between groups pairwise comparison of mean pump flow. Results: Initial pump flow (A) was 4.3±0.6 L/min dropping to 2.8±0.7 L/min (P B-A= 0.003) 10 minutes after induction of ventricular fibrillation (B). After cardiectomy, with the pulmonary artery clamped (C) it augmented not significantly to 3.5±0.8 L/min (P C-B= 0.33, P C-A= 0.029). Finally, PA anastomosis to the caval axis was followed by an almost to baseline pump flow augmentation (4.1±0.7 L/min, P D-B= 0.009, P D-C= 0.006, P D-A= 0.597), permitting a full ECMO support in acardia by a peripheral vascular access. Conclusions: ECMO support in acardia is feasible, providing new opportunities in situations where heart must urgently be explanted, as in hyperacute rejection of heart transplant. Adequate drainage of pulmonary circulation is pivotal in order to avoid pulmonary congestion and loss of volume from the normal right to left shunt of bronchial vessels. Furthermore, the PA anastomosis to the caval axis not only improves pump flow but it also permits an ECMO support by a peripheral vascular access and the closure of the chest.

Angiotensin II favors progression to heart failure in diabetic hearts: role of myocardial fatty acid oxidation downregulation

Purpose: Diabetic myocardium is particularly vulnerable to develop heart failure in response to chronic stress conditions including hypertension or myocardial infarction. We have recently observed that angiotensin II (Ang II)-mediated downregulation of the fatty acid oxidation pathway favors occurrence of heart failure by myocardial accumulation of lipids (lipotoxicity). Because diabetic heart is exposed to high levels of circulating fatty acid, we determined whether insulin resistance favors development of heart failure in mice with Ang II-mediated myocardial remodeling.Methods: To study the combined effect of diabetes and Ang II-induced heart remodeling, we generated leptin-deficient/insulin resistant (Lepob/ob) mice with cardiac targeted overexpression of angiotensinogen (TGAOGN). Left ventricular (LV) failure was indicated by pulmonary congestion (lung weight/tibial length>+2SD of wild-type mice). Myocardial metabolism and function were assessed during in vitro isolated working heart perfusion.Results: Forty-eight percent of TGAOGN mice without insulin resistance exhibited pulmonary congestion at the age of 6 months associated with increased myocardial BNP expression (+375% compared with WT) and reduced LV power (developed pressure x cardiac output; -15%). The proportion of mice presenting heart failure was markedly increased to 71% in TGAOGN mice with insulin resistance (TGAOGN/Lepob/ob). TGAOGN/Lepob/ob mice with heart failure exhibited further increase of BNP compared with failing non-diabetic TGAOGN mice (+146%) and further reduction of cardiac power (-59%). Mice with insulin resistance alone (Lepob/ob) did not exhibit signs of heart failure or LV dysfunction. Myocardial fatty acid oxidation measured during in vitro perfusion was markedly increased in non-failing hearts from Lepob/ob mice (+380% compared with WT) and glucose oxidation decreased (-72%). In contrast, fatty acid and glucose oxidation did not differ from Lepob/ob mice in hearts from TGAOGN/Lepob/ob mice without heart failure. However, both fatty acid and glucose oxidation were markedly decreased (-47% and -48%, respectively, compared with WT/Lepob/+) in failing hearts from TGAOGN/Lepob/ob mice. Reduction of fatty acid oxidation was associated with marked reduction of protein expression of a number of regulatory enzymes implied in fatty acid oxidation.Conclusions: Insulin resistance favors the progression to heart failure during chronic exposure of the myocardium to Ang II. Our results are compatible with a role of Ang II-mediated downregulation of fatty acid oxidation, potentially promoting lipotoxicity.