Galectin-3: A Link between Myocardial and Arterial Stiffening in Patients with Acute Decompensated Heart Failure?

Abstract Background: Heart failure is accompanied by abnormalities in ventricular-vascular interaction due to increased myocardial and arterial stiffness. Galectin-3 is a recently discovered biomarker that plays an important role in myocardial and vascular fibrosis and heart failure progression. Objectives: The aim of this study was to determine whether galectin-3 is correlated with arterial stiffening markers and impaired ventricular-arterial coupling in decompensated heart failure patients. Methods: A total of 79 inpatients with acute decompensated heart failure were evaluated. Serum galectin-3 was determined at baseline, and during admission, transthoracic echocardiography and measurements of vascular indices by Doppler ultrasonography were performed. Results: Elevated pulse wave velocity and low arterial carotid distensibility are associated with heart failure in patients with preserved ejection fraction (p = 0.04, p = 0.009). Pulse wave velocity, carotid distensibility and Young’s modulus did not correlate with serum galectin-3 levels. Conversely, raised galectin-3 levels correlated with an increased ventricular-arterial coupling ratio (Ea/Elv) p = 0.047, OR = 1.9, 95% CI (1.0‑3.6). Increased galectin-3 levels were associated with lower rates of left ventricular pressure rise in early systole (dp/dt) (p=0.018) and raised pulmonary artery pressure (p = 0.046). High galectin-3 levels (p = 0.038, HR = 3.07) and arterial pulmonary pressure (p = 0.007, HR = 1.06) were found to be independent risk factors for all-cause mortality and readmissions. Conclusions: This study showed no significant correlation between serum galectin-3 levels and arterial stiffening markers. Instead, high galectin-3 levels predicted impaired ventricular-arterial coupling. Galectin-3 may be predictive of raised pulmonary artery pressures. Elevated galectin-3 levels correlate with severe systolic dysfunction and together with pulmonary hypertension are independent markers of outcome.

Soluble ST2 Testing: A Promising Biomarker in the Management of Heart Failure

Abstract ST2 is a member of the interleukin-1 receptor family biomarker and circulating soluble ST2 concentrations are believed to reflect cardiovascular stress and fibrosis. Recent studies have demonstrated soluble ST2 to be a strong predictor of cardiovascular outcomes in both chronic and acute heart failure. It is a new biomarker that meets all required criteria for a useful biomarker. Of note, it adds information to natriuretic peptides (NPs) and some studies have shown it is even superior in terms of risk stratification. Since the introduction of NPs, this has been the most promising biomarker in the field of heart failure and might be particularly useful as therapy guide.

Analysis Treatment Guideline versus Clinical Practice Protocol in Patients Hospitalized due to Heart Failure

Background: Despite the availability of guidelines for treatment of heart failure (HF), only a few studies have assessed how hospitals adhere to the recommended therapies. Objectives: Compare the rates of adherence to the prescription of angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers (ACEI/ARB) at hospital discharge, which is considered a quality indicator by the Joint Commission International, and to the prescription of beta-blockers at hospital discharge, which is recommended by national and international guidelines, in a hospital with a case management program to supervise the implementation of a clinical practice protocol (HCP) and another hospital that follows treatment guidelines (HCG). Methods: Prospective observational study that evaluated patients consecutively admitted to both hospitals due to decompensated HF between August 1st, 2006, and December 31st, 2008. We used as comparing parameters the prescription rates of beta-blockers and ACEI/ARB at hospital discharge and in-hospital mortality. Results: We analyzed 1,052 patients (30% female, mean age 70.6 ± 14.1 years), 381 (36%) of whom were seen at HCG and 781 (64%) at HCP. The prescription rates of beta-blockers at discharge at HCG and HCP were both 69% (p = 0.458), whereas those of ACEI/ARB were 83% and 86%, respectively (p = 0.162). In-hospital mortality rates were 16.5% at HCP and 27.8% at HCG (p < 0.001). Conclusion: There was no difference in prescription rates of beta-blocker and ACEI/ARB at hospital discharge between the institutions, but HCP had lower in-hospital mortality. This difference in mortality may be attributed to different clinical characteristics of the patients in both hospitals.

Prognostic Value of Pulmonary Vascular Resistance by Magnetic Resonance in Systolic Heart Failure

Abstract Background: Pulmonary hypertension is associated with poor prognosis in heart failure. However, non-invasive diagnosis is still challenging in clinical practice. Objective: We sought to assess the prognostic utility of non-invasive estimation of pulmonary vascular resistances (PVR) by cardiovascular magnetic resonance to predict adverse cardiovascular outcomes in heart failure with reduced ejection fraction (HFrEF). Methods: Prospective registry of patients with left ventricular ejection fraction (LVEF) < 40% and recently admitted for decompensated heart failure during three years. PVRwere calculated based on right ventricular ejection fraction and average velocity of the pulmonary artery estimated during cardiac magnetic resonance. Readmission for heart failure and all-cause mortality were considered as adverse events at follow-up. Results: 105 patients (average LVEF 26.0 ±7.7%, ischemic etiology 43%) were included. Patients with adverse events at long-term follow-up had higher values of PVR (6.93 ± 1.9 vs. 4.6 ± 1.7estimated Wood Units (eWu), p < 0.001). In multivariate Cox regression analysis, PVR ≥ 5 eWu(cutoff value according to ROC curve) was independently associated with increased risk of adverse events at 9 months follow-up (HR2.98; 95% CI 1.12-7.88; p < 0.03). Conclusions: In patients with HFrEF, the presence of PVR ≥ 5.0 Wu is associated with significantly worse clinical outcome at follow-up. Non-invasive estimation of PVR by cardiac magnetic resonance might be useful for risk stratification in HFrEF, irrespective of etiology, presence of late gadolinium enhancement or LVEF.

Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction

Abstract Background: More than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties. Objectives: To evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF. Methods: Twenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months. Results: After treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters. Conclusion: Despite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity.

Association between Spirituality and Adherence to Management in Outpatients with Heart Failure

Abstract Background: Spirituality may influence how patients cope with their illness. Objectives: We assessed whether spirituality may influence adherence to management of outpatients with heart failure. Methods: Cross sectional study enrolling consecutive ambulatory heart failure patients in whom adherence to multidisciplinary treatment was evaluated. Patients were assessed for quality of life, depression, religiosity and spirituality utilizing validated questionnaires. Correlations between adherence and psychosocial variables of interest were obtained. Logistic regression models explored independent predictors of adherence. Results: One hundred and thirty patients (age 60 ± 13 years; 67% male) were interviewed. Adequate adherence score was observed in 38.5% of the patients. Neither depression nor religiosity was correlated to adherence, when assessed separately. Interestingly, spirituality, when assessed by both total score sum (r = 0.26; p = 0.003) and by all specific domains, was positively correlated to adherence. Finally, the combination of spirituality, religiosity and personal beliefs was an independent predictor of adherence when adjusted for demographics, clinical characteristics and psychosocial instruments. Conclusion: Spirituality, religiosity and personal beliefs were the only variables consistently associated with compliance to medication in a cohort of outpatients with heart failure. Our data suggest that adequately addressing these aspects on patient’s care may lead to an improvement in adherence patterns in the complex heart failure management.

Estudos experimentais sôbre a origem do milho

1) It may seem rather strange that, in spite of the efforts of a considerable number of scientists, the problem of the origin of indian corn or maize still has remained an open question. There are no fossil remains or archaeological relics except those which are quite identical with types still existing. (Fig. 1). The main difficulty in finding the wild ancestor- which may still exist - results from the fact that it has been somewhat difficult to decide what it should be like and also where to look for it. 2) There is no need to discuss the literature since an excellent review has recently been published by MANGELSDORF and REEVES (1939). It may be sufficient to state that there are basically two hypotheses, that of ST. HILAIRE (1829) who considered Brazilian pod corn as the nearest relative of wild corn still existing, and that of ASCHERSON (1875) who considered Euchlaena from Central America as the wild ancestor of corn. Later hypotheses represent or variants of these two hypotheses or of other concepts, howewer generally with neither disproving their predecessors nor showing why the new hypotheses were better than the older ones. Since nearly all possible combinations of ideas have thus been put forward, it har- dly seems possible to find something theoretically new, while it is essential first to produce new facts. 3) The studies about the origin of maize received a new impulse from MANGELSDORF and REEVES'S experimental work on both Zea-Tripsacum and Zea-Euchlaena hybrids. Independently I started experiments in 1937 with the hope that new results might be obtained when using South American material. Having lost priority in some respects I decided to withold publication untill now, when I can put forward more concise ideas about the origin of maize, based on a new experimental reconstruction of the "wild type". 4) The two main aspects of MANGELSDORF and REEVES hypothesis are discussed. We agree with the authors that ST. HILAIRE's theory is probably correct in so far as the tunicata gene is a wild type relic gene, but cannot accept the reconstruction of wild corn as a homozygous pod corn with a hermaphroditic tassel. As shown experimentally (Fig. 2-3) these tassels have their central spike transformed into a terminal, many rowed ear with a flexible rachis, while possessing at the same time the lateral ear. Thus no explanation is given of the origin of the corn ear, which is the main feature of cultivated corn (BRIEGER, 1943). The second part of the hypothesis referring to the origin of Euchlaena from corn, inverting thus ASCHERSON's theory, cannot be accepted for several reasons, stated in some detail. The data at hand justify only the conclusion that both genera, Euchlaena and Zea, are related, and there is as little proof for considering the former as ancestor of the latter as there is for the new inverse theory. 5) The analysis of indigenous corn, which will be published in detail by BRIEGER and CUTLER, showed several very primitive characters, but no type was found which was in all characters sufficiently primitive. A genetical analysis of Paulista Pod Corn showed that it contains the same gene as other tunicates, in the IV chromosome, the segregation being complicated by a new gametophyte factor Ga3. The full results of this analysis shall be published elsewhere. (BRIEGER). Selection experiments with Paulista Pod Corn showed that no approximation to a wild ancestor may be obtained when limiting the studies to pure corn. Thus it seemed necessary to substitute "domesticated" by "wild type" modifiers, and the only means for achieving this substitution are hybridizations with Euchlaena. These hybrids have now been analysed init fourth generation, including backcrosses, and, again, the full data will be published elsewhere, by BRIEGER and ADDISON. In one present publication three forms obtained will be described only, which represent an approximation to wild type corn. 6) Before entering howewer into detail, some arguments against ST. HILAIRE's theory must be mentioned. The premendelian argument, referring to the instability of this character, is explained by the fact that all fertile pod corn plants are heterozygous for the dominant Tu factor. But the sterility of the homozygous TuTu, which phenotypically cannot be identified, is still unexplained. The most important argument against the acceptance of the Tunicata faetor as wild type relic gene was removed recently by CUTLER (not yet published) who showed that this type has been preserved for centuries by the Bolivian indians as a mystical "medicine". 7) The main botanical requirements for transforming the corn ear into a wild type structure are stated, and alternative solutions given. One series of these characters are found in Tripsacum and Euchlaena : 2 rows on opposite sides of the rachis, protection of the grains by scales, fragility of the rachis. There remains the other alternative : 4 rows, possibly forming double rows of female and male spikelets, protection of kernels by their glumes, separation of grains at their base from the cob which is thin and flexible. 8) Three successive stages in the reconstruction of wild corn, obtained experimentally, are discussed and illustrated, all characterized by the presence of the Tu gene. a) The structure of the Fl hybrids has already been described in 1943. The main features of the Tunicata hybrids (Fig. -8), when compared with non-tunicate hybrids (Fig. 5-6), consist in the absence of scaly protections, the fragility of the rachis and finally the differentiation of the double rows into one male and one female spikelet. As has been pointed out, these characters represent new phenotypic effects of the tunicate factor which do not appear in the presence of pure maize modifiers. b) The next step was observed among the first backcross to teosinte (Fig. 9). As shown in the photography, Fig. 9D, the features are essencially those of the Fl plants, except that the rachis is more teosinte like, with longer internodes, irregular four-row-arrangement and a complete fragility on the nodes. c) In the next generation a completely new type appeared (Fig. 10) which resembles neither corn nor teosinte, mainly in consequence of one character: the rachis is thin and flexible and not fragile, while the grains have an abscission layer at the base, The medium sized, pointed, brownish and hard granis are protected by their well developed corneous glumes. This last form may not yet be the nearest approach to a wild grass, and I shall try in further experiments to introduce other changes such as an increase of fertile flowers per spikelet, the reduction of difference between terminal and lateral inflorescences, etc.. But the nature of the atavistic reversion is alveadwy such that it alters considerably our expectation when looking for a still existing wild ancestor of corn. 9) The next step in our deductions must now consist in an reversion of our question. We must now explain how we may obtain domesticated corn, starting from a hypothetical wild plant, similar to type c. Of the several changes which must have been necessary to attract the attention of the Indians, the following two seem to me the most important: the disappearance of all abscission layers and the reduction of the glumes. This may have been brought about by an accumulation of mutations. But it seems much more probable to assume that some crossing with a tripsacoid grass or even with Tripsacum australe may have been responsible. In such a cross, the two types of abscission layer would be counterbalanced as shown by the Flhybrids of corn, Tripsacum and Euchlaena. Furthermore in later generations a.tu-allele of Tripsacum may become homozygous and substitute the wild tunicate factor of corn. The hypothesis of a hybrid origin of cultivated corn is not completely new, but has been discussed already by HARSHBERGER and COLLINS. Our hypothesis differs from that of MANGELSDORF and REEVES who assume that crosses with Tripsacum are responsible only for some features of Central and North American corn. 10) The following arguments give indirects evidence in support of our hypothesis: a) Several characters have been observed in indigenous corn from the central region of South America, which may be interpreted as "tripsacoid". b) Equally "zeoid" characters seem to be present in Tripsacum australe of central South-America. c) A system of unbalanced factors, combined by the in-tergeneric cross, may be responsible for the sterility of the wild type tunicata factor when homozygous, a result of the action of modifiers, brought in from Tripsacum together with the tuallele. d) The hybrid theory may explain satisfactorily the presence of so many lethals and semilethals, responsible for the phenomenon of inbreeding in cultivated corn. It must be emphasized that corn does not possess any efficient mechanism to prevent crossing and which could explain the accumulation of these mutants during the evolutionary process. Teosinte which'has about the same mechanism of sexual reproduction has not accumulated such genes, nor self-sterile plants in spite of their pronounced preference for crossing. 11) The second most important step in domestication must have consisted in transforming a four rowed ear into an ear with many rows. The fusion theory, recently revived byLANGHAM is rejected. What happened evidently, just as in succulent pXants (Cactus) or in cones os Gymnosperms, is that there has been a change in phyllotaxy and a symmetry of longitudinal rows superimposed on the original spiral arrangement. 12) The geographical distribution of indigenous corn in South America has been discussed. So far, we may distinguish three zones. The most primitive corn appears in the central lowlands of what I call the Central Triangle of South America: east of the Andies, south of the Amazone-Basin, Northwest of a line formed by the rivers São Prancisco-Paraná and including the Paraguay-Basin. The uniformity of the types found in this extremely large zone is astonishing (BRIEGER and CUTLER). To the west, there is the well known Andian region, characterized by a large number of extremely diverse types from small pop corn to large Cuszco, from soft starch to modified sweet corn, from large cylindrical ears to small round ears, etc.. The third region extends along the atlantic coast in the east, from the Caribean Sea to the Argentine, and is characterized by Cateto, an orange hard flint corn. The Andean types must have been obtained very early, and undoubtedly are the result of the intense Inca agriculture. The Cateto type may be obtained easily by crosses, for instance, of "São Paulo Pointed Pop" to some orange soft corn of the central region. The relation of these three South American zones to Central and North America are not discussed, and it seems essential first to study the intermediate region of Ecuador, Colombia and Venezuela. The geograprical distribution of chromosome knobs is rapidly discussed; but it seems that no conclusions can be drawn before a large number of Tripsacum species has been analysed.

Prevention of bone marrow graft failure by an anti LFA-1 monoclonal antibody

Graft rejection is the major cause of failure of HLA mismatched bone marrow transplantation because of residual host immunity. we have proposed to use a monoclonal murine antibody specific for the LFA-1 molecule (25-3) to prevent graft failure in HLA mismatched bone marrow transplantation (BMT). The rationale for this approach is three fold: LFA-1 deficient patients (3/3) do not reject HLA mismatched BMT; anti LFA-1 blocka in vitro the induction of T cell responses and T/ non T cytotoxic functions; LFA-1 is not expressed by other cells than leucocytes. We have accordingly treated twenty two patients with inherited diseases and 8 with leikemia. The bone marrow was T cells depled by E rosetting of Campath antibody. The antibody was given at days -3, -1, +1, +3, +5 at dose of .1 mg/kg/d for the first 9 and then .2mg/kg/d from day -3 to +6. Engraftment occured in 23/30 patients as shown by at least HLA typing. Hematological recovery was rapid, GVH was limited. Side effects of antibody infusion included fever and possibly an increased incidence of early bacteral infection (sepsis, 1 death). Immunological reconstitution occured slowly leading in six cases to EBV-induced B cell poliferation (1 death and in two others to transient auto immune hemolytic anemia. There has been only one secondary graft rejection. Sisteen patients are alive 3 to 26 months post transplant with functional grafts. Although the number of patients treated is still low the absence of late rejection so far, gives hope for long term maintenance of the graft using anti LFA-1. Since the antibody is an IgG 1 unable to bind human complement, and since it is known to inhibit phagocytosis, there is a good suggestion that 25-3 act through functional blocking of host T and non T luymphocytes at both induction and effector levels.

Experimental toxoplasmosis in Balb/c mice. Prevention of vertical disease transmission by treatment and reproductive failure in chronic infection

In a study of congenital transmission during acute infection of Toxoplasma gondii, 23 pregnant Balb/c mice were inoculated orally with two cysts each of the P strain. Eight mice were inoculated 6-11 days after becoming pregnant (Group 1). Eight mice inoculated on the 10th-15th day of pregnancy (Group 2) were treated with 100 mg/kg/day of minocycline 48 h after inoculation. Seven mice inoculated on the 10th-15th day of pregnancy were not treated and served as a control (Group 3). Congenital transmission was evaluated through direct examination of the brains of the pups or by bioassay and serologic tests. Congenital transmission was observed in 20 (60.6%) of the 33 pups of Group 1, in one (3.6%) of the 28 pups of Group 2, and in 13 (54.2%) of the 24 pups of Group 3. Forty-nine Balb/c mice were examined in the study of congenital transmission of T. gondii during chronic infection. The females showed reproductive problems during this phase of infection. It was observed accentuated hypertrophy of the endometrium and myometrium. Only two of the females gave birth. Our results demonstrate that Balb/c mice with acute toxoplasmosis can be used as a model for studies of congenital T. gondii infection. Our observations indicate the potential of this model for testing new chemotherapeutic agents against congenital toxoplasmosis.

Study of Schistosoma mansoni isolates from patients with failure of treatment with oxamniquine

After three successive treatments with oxamniquine the continuing elimination of Schistosoma mansoni eggs was observed in patients, who came from various regions of Brazil, with different clinical forms of schistosomiasis. The objective of the present study was to determine the experimental behaviour of five different S. mansoni isolates in Swiss Webster mice that were submitted to treatment with the same drug. The experimental group with failure of treatment showed higher mean number of surviving male worms when it was compared to the group without failure of treatment. These date suggest the possibility of resistance to oxamniquine.