Repetitive levosimendan treatment in the management of advanced heart failure

Inotropes may be an appropriate treatment for patients with advanced heart failure (AdHF) who remain highly symptomatic despite optimized standard therapies. Objectives for inotrope use in these situations include relief of symptoms and improvement of quality of life, and reduction in unplanned hospitalizations and the costs associated with such episodes. All of these goals must be attained without compromising survival. Encouraging findings with intermittent cycles of intravenous levosimendan have emerged from a range of exploratory studies and from three larger controlled trials (LevoRep, LION-HEART, and LAICA) which offered some evidence of clinical advantage. In these settings, however, obtaining statistically robust data may prove elusive due to the difficulties of endpoint assessment in a complex medical condition with varying presentation and trajectory. Adoption of a composite clinical endpoint evaluated in a hierarchical manner may offer a workable solution to this problem. Such an instrument can explore the proposition that repetitive administration of levosimendan early in the period after discharge from an acute episode of worsening heart failure may be associated with greater subsequent clinical stability vis-à-vis standard therapy. The use of this methodology to develop a 'stability score' for each patient means that all participants in such a trial contribute to the overall outcome analysis through one or more of the hierarchical endpoints; this has helpful practical implications for the number of patients needed and the length of follow-up required to generate endpoint data. The LeoDOR study (NCT03437226), outlined in this review, has been designed to explore this new approach to outcome assessment in AdHF

Gene Deletion of the Kinin Receptor B1 Attenuates Cardiac Inflammation and Fibrosis During the Development of Experimental Diabetic Cardiomyopathy

Objective: Diabetic cardiomyopathy is associated with increased mortality in patients with diabetes mellitus. The underlying pathology of this disease is still under discussion. We studied the role of the kinin B1 receptor on the development of experimental diabetic cardiomyopathy. Research Design and Methods: We utilized B1 receptor knockout mice and investiged cardiac inflammation, fibrosis and oxidative stress after induction of streptozotocin (STZ)-induced diabetes mellitus. Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes mellitus. Results: B1 receptor knockout mice showed an attenuation of diabetic cardiomyopathy with improved systolic and diastolic function in comparison with diabetic control mice. This was associated with a decreased activation state of the MAP kinase p38, less oxidative stress as well as normalized cardiac inflammation, shown by fewer invading cells and, no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5. Furthermore, the pro-fibrotic connective tissue growth factor was normalized, leading to a reduction in cardiac fibrosis despite severe hyperglycemia in mice lacking the B1 receptor. Conclusion: These findings suggest that the B1 receptor is detrimental in diabetic cardiomyopathy in that it mediates inflammatory and fibrotic processes. These insights might have useful implications on future studies utilizing B1 receptor antagonists for treatment of human diabetic cardiomyopathy

Distribuição de frequência da altura do capim-marandu sob lotação contínua e taxa de lotação variável em sistemas de produção animal.

PT-BR: O objetivo desse estudo foi descrever e explicar a distribuição da frequência da altura do capim-marandu (Brachiaria brizantha cv. Marandu) sob lotação contínua e taxa de lotação variável em sistemas de produção animal. O experimento foi em delineamento em blocos completos casualizados, com avaliação de 2 sistemas de produção em 4 repetições. A distribuição da altura foi caracterizada com auxílio de histogramas, e os parâmetros média, moda, assimetria e curtose foram calculados para cada tratamento. A altura nos sistemas de produção foi semelhante (p = 0,888) com média de 37 cm. Os sistemas silvipastoril e pecuária tiveram distribuição acentuada (0,44 e 0,47 de curtose, respectivamente). A assimetria do sistema silvipastoril foi 0,209614 e da pecuária foi de -0,19529, valores considerados normais. Para o período avaliado, a distribuição da altura nos sistemas de produção silvipastoril e pecuária não distinguiram, possivelmente, devido ao sistema silvipastoril ter níveis de radiação adequados para desenvolvimento da forragem. | EN: The objective with this study was to describe and explain the frequency distribution of marandu palisade grass (Brachiaria brizantha cv. Marandu) under continuous stocking rate and variable stocking rate in animal production systems. The experiment was a randomized complete block design, with 2 production systems in 4 replicates. The height distribution was characterized using histograms, and the mean, mode, skewness and kurtosis parameters were calculated for each system. The sward height was similar in the systems (p = 0.888), with 37 cm. Both treatments had a marked distribution (0.44 and 0.47 of kurtosis for silvopastoral and livestock systems, respectively). The asymmetry of the silvopastoral system was 0.209614 and livestock systems was -0.1959, which were considered normal. For the period evaluated, the height distribution in silvopastoral and livestock production systems did not distinguish, possibly due to the silvopastoral system, which have enough radiation levels for forage development

Métodos para mensuração da altura em capim-marandu sob pastejo em lotação contínua e taxa de lotação variável em sistemas integrados.

PT-BR: Métodos que sejam capazes de mensurar com acurácia a altura do dossel são necessários para que ajustes da taxa de lotação animal em sistemas silvipastoril. O objetivo foi comparar métodos para mensuração da altura do dossel forrageiro em sistemas silvipastoril manejados sob lotação contínua e taxa de lotação variável. O delineamento foi em blocos completos casualizados, com avaliação de dois métodos (?zig zag? e sistematizado) para determinação da altura do dossel, em dois sistemas silvipastoril. Não houve diferença (p = 0,4015) entre os métodos de mensuração da altura do dossel no sistema silvipastoril. A altura média do dossel foi de 35,06 cm (erro padrão da média = 0,6138 cm). Independentemente do método utilizado para avaliação da altura do dossel forrageiro do capim-marandu no sistema silvipastoril, não há distinção entre métodos. | EN: Methods that are able to measure of the canopy height with accuracy are necessary for adjustments of the animal stocking rate in silvopastoral systems. The objective was to compare methods of canopy height measuring in silvopastoral systems managed under continuous stocking and variable stocking rate. The design was in randomized complete blocks, with evaluation of two methods (?zig zag? and systematized) was used to determine the canopy height in two silvopastoral systems. There was no difference (p = 0.4015) between the canopy height measurement methods in the silvopastoral system. The average height of the canopy was 35.06 cm (standard error of the mean = 0.6138 cm). Regardless of the method used to evaluate the height of the forage canopy of the marandu palisadgrass in the silvopastoral system, there is no distinction between methods

Case Report First-in-Man Method Description: Left Ventricular Unloading With iVAC2L During Veno-Arterial Extracorporeal Membrane Oxygenation

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is increasingly used in bi-ventricular failure with cardiogenic shock to maintain systemic perfusion. Nonetheless, it tends to increase left ventricular (LV) afterload and myocardial oxygen demand. In order to mitigate these negative effects on the myocardium, an Impella CP® (3.5 L/min Cardiac Output) can be used in conjunction with V-A ECMO (ECMELLA approach). We implemented this strategy in a patient with severe acute myocarditis complicated by cardiogenic shock. Due to a hemolysis crisis, Impella CP® had to be substituted with PulseCath iVAC2L®, which applies pulsatile flow to unload the LV. A subsequent improvement in LV systolic function was noted, with increased LV ejection fraction (LVEF), LV end-diastolic diameter (LVEDD) reduction, and a reduction in plasma free hemoglobin. This case documents the efficacy of iVAC2L in replacing Impella CP as a LV vent during V-A ECMO, with less hemolysis

Myocarditis following COVID-19 vaccine: incidence, presentation, diagnosis, pathophysiology, therapy, and outcomes put into perspective. A clinical consensus document supported by the Heart Failure Association of the European Society of Cardiology (ESC) and the ESC Working Group on Myocardial and Pericardial Diseases

Over 10 million doses of COVID-19 vaccines based on RNA technology, viral vectors, recombinant protein, and inactivated virus have been administered worldwide. Although generally very safe, post-vaccine myocarditis can result from adaptive humoral and cellular, cardiac-specific inflammation within days and weeks of vaccination. Rates of vaccine-associated myocarditis vary by age and sex with the highest rates in males between 12 and 39 years. The clinical course is generally mild with rare cases of left ventricular dysfunction, heart failure and arrhythmias. Mild cases are likely underdiagnosed as cardiac magnetic resonance imaging (CMR) is not commonly performed even in suspected cases and not at all in asymptomatic and mildly symptomatic patients. Hospitalization of symptomatic patients with electrocardiographic changes and increased plasma troponin levels is considered necessary in the acute phase to monitor for arrhythmias and potential decline in left ventricular function. In addition to evaluation for symptoms, electrocardiographic changes and elevated troponin levels, CMR is the best non-invasive diagnostic tool with endomyocardial biopsy being restricted to severe cases with heart failure and/or arrhythmias. The management beyond. guideline-directed treatment of heart failure and arrhythmias includes non-specific measures to control pain. Anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs, and corticosteroids have been used in more severe cases, with only anecdotal evidence for their effectiveness. In all age groups studied, the overall risks of SARS-CoV-2 infection-related hospitalization and death are hugely greater than the risks from post-vaccine myocarditis. This consensus statement serves as a practical resource for physicians in their clinical practice, to understand, diagnose, and manage affected patients. Furthermore, it is intended to stimulate research in this area

Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment

Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF

Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy

Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1β, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1β secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1β- positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation