Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment ...with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure.
In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 μg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days.
A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval CI, 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups.
In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).
Heart failure with preserved ejection fraction (HFpEF) is considered to be the dominant cause of dyspnea and pulmonary hypertension (PH) in elderly patients with preserved left ventricular systolic ...function and cardiovascular comorbidities. However, it is important to keep in mind that left ventricular diastolic dysfunction is not the only possible cause of PH in cases of late-onset clinical manifestation. A multiparametric approach is essential for accurate diagnosis and therapeutic decision-making. A 74-year-old patient was admitted due to progressive dyspnea and suspicion of PH. Given the patient's risk profile, HFpEF and concomitant post-capillary PH were anticipated. Despite negative findings on CT angiography and transesophageal echocardiography, right heart catheterization was performed, revealing discrepant oxygen saturations in the superior vena cava and right atrium. A partial anomalous pulmonary venous return and an atrial septal defect were identified through cardiac magnetic resonance imaging.
Guideline‐directed medical therapy (GDMT) has the potential to reduce the risks of mortality and hospitalisation in patients with heart failure (HF) with reduced ejection fraction (HFrEF). However, ...real‐world data indicate that many patients with HFrEF do not receive optimised GDMT, which involves several different medications, many of which require up‐titration to target doses. There are many challenges to implementing GDMT, the most important being patient‐related factors (comorbidities, advanced age, frailty, cognitive impairment, poor adherence, low socioeconomic status), treatment‐related factors (intolerance, side‐effects) and healthcare‐related factors that influence availability and accessibility of HF care. Accordingly, international disparities in resources for HF management and limited public reimbursement of GDMT, coupled with clinical inertia for treatment intensification combine to hinder efforts to provide GDMT. In this review paper, authors aim to provide solutions based on available evidence, practical experience, and expert consensus on how to utilise evolving strategies, novel medications, and patient profiling to allow the more comprehensive uptake of GDMT. Authors discuss professional education, motivation, and training, as well as patient empowerment for self‐care as important tools to overcome clinical inertia and boost GDMT implementation. We provide evidence on how multidisciplinary care and institutional accreditation can be successfully used to increase prescription rates and adherence to GDMT. We consider the role of modern technologies in advancing professional and patient education and facilitating patient–provider communication. Finally, authors emphasise the role of novel drugs (especially sodium–glucose co‐transporter 2 inhibitors), and a tailored approach to drug management as evolving strategies for the more successful implementation of GDMT.
Improvement of left ventricular ejection fraction (LVEF) in patients after the first manifestation of heart failure with reduced ejection fraction (HFrEF) has currently been observed more frequently ...than it was years ago. This appears to be due to the early initiation of comprehensive HF therapy. According to these observations, a new HF syndrome category, heart failure with improved ejection fraction (HFimpEF), was introduced. In this short review, we present definitions of reverse remodelling, myocardial remission, and myocardial recovery. We provide an overview of clinical research aimed at evaluating reverse remodelling in different populations of patients with HFrEF. Clinical and imaging characteristics and biomarkers identified as predictors of reverse remodelling and improvement of the LVEF are discussed. We also briefly address the current views on the management of patients with HFimpEF. In-depth study and knowledge of the molecular mechanisms underlying the reverse remodelling process may lead to the identification of new individualized therapeutic approaches for HFrEF.
Scimitar syndrome is a congenital disorder characterized by partial anomalous pulmonary venous return to the inferior vena cava (IVC). Clinical manifestation in adulthood is infrequent. The ...management approach has not been universally accepted and may be challenging. Individually tailored and multidisciplinary team-based decisions are often necessary. We present the case of a symptomatic patient diagnosed with complex congenital heart disease, including scimitar syndrome and atrial septal defect at the age of 50 years. Surgical repair, involving scimitar vein implantation in the left atrium using a pericardial patch, was performed. Despite surgical correction, dyspnea persisted, and hemoptysis developed. A diagnostic workup revealed a critical stenosis of the re-inserted vein. This was successfully treated by percutaneous intervention with stent implantation. The patient has remained asymptomatic since the procedure. Scimitar syndrome can be first diagnosed in adulthood, and clinical manifestations can vary. Diagnostic workup necessitates a CT angiogram, magnetic resonance scan, and catheterization in selected cases. Stenoses of re-implanted pulmonary veins (PVs) can develop years after surgical correction, and hemoptysis may serve as a warning symptom prompting further PV imaging. Percutaneous vascular intervention using a stent is warranted in symptomatic cases and can lead to long-term success.Scimitar syndrome is a congenital disorder characterized by partial anomalous pulmonary venous return to the inferior vena cava (IVC). Clinical manifestation in adulthood is infrequent. The management approach has not been universally accepted and may be challenging. Individually tailored and multidisciplinary team-based decisions are often necessary. We present the case of a symptomatic patient diagnosed with complex congenital heart disease, including scimitar syndrome and atrial septal defect at the age of 50 years. Surgical repair, involving scimitar vein implantation in the left atrium using a pericardial patch, was performed. Despite surgical correction, dyspnea persisted, and hemoptysis developed. A diagnostic workup revealed a critical stenosis of the re-inserted vein. This was successfully treated by percutaneous intervention with stent implantation. The patient has remained asymptomatic since the procedure. Scimitar syndrome can be first diagnosed in adulthood, and clinical manifestations can vary. Diagnostic workup necessitates a CT angiogram, magnetic resonance scan, and catheterization in selected cases. Stenoses of re-implanted pulmonary veins (PVs) can develop years after surgical correction, and hemoptysis may serve as a warning symptom prompting further PV imaging. Percutaneous vascular intervention using a stent is warranted in symptomatic cases and can lead to long-term success.
Cell loss and subsequent deterioration of contractile function are hallmarks of chronic heart failure (HF). While apoptosis has been investigated as a participant in the progression of HF, it is ...unlikely that it accounts for the total amount of non-functional tissue. In addition, there is evidence for the presence of necrotic cardiomyocytes in HF. Therefore, the objective of this study was to investigate the necroptotic proteins regulating necroptosis, a form of programmed necrosis, and thereby assess its potential role in human end-stage HF.
Left ventricular samples of healthy controls (C) and patients with end-stage HF due to myocardial infarction (CAD) or dilated cardiomyopathy (DCM) were studied. Immunoblotting for necroptotic and apoptotic markers was performed. Triton X-114 fractionated samples were analyzed to study differences in subcellular localization.
Elevated expression of RIP1 (receptor-interacting protein), pSer
-RIP3 and its total levels were observed in HF groups compared to controls. On the other hand, caspase-8 expression, a proapoptotic protease negatively regulating necroptosis, was downregulated suggesting activation of necroptosis signaling. Total mixed-lineage kinase domain-like protein (MLKL) expression did not differ among the groups; however, active cytotoxic forms of MLKL were present in all HF samples while they were expressed at almost undetectable levels in controls. Interestingly, pThr
-MLKL unlike pSer
-MLKL, was higher in DCM than CAD. In HF, the subcellular localization of both RIP3 and pThr
-MLKL was consistent with activation of necroptosis signaling. Expression of main apoptotic markers has not indicated importance of apoptosis.
This is the first evidence showing that human HF of CAD or DCM etiology is positive for markers of necroptosis which may be involved in the development of HF.
As necroptosis involving receptor-interacting protein kinase 3 (RIP3) and dynamin-related protein 1 (Drp1)-mediated signalling is a crucial mechanism of cell loss in heart failure (HF), we aimed to ...determine the potential diagnostic use of these molecules.
The serum samples of the healthy subjects (n = 8) and patients with HF with reduced ejection fraction (n = 31), being subdivided according to the aetiology and New York Heart Association (NYHA) class, were used to measure RIP3 and Drp1 levels by enzyme-linked immunosorbent assay. Although the serum levels of Drp1 in the patients with HF were comparable with those seen in healthy individuals, we found a trend of increase in the levels of RIP3 (P = 0.0697) in the diseased group. These changes were unlikely dependent on the HF aetiology or NYHA class. The circulating RIP3 correlated with neither the main parameters assessing cardiac function (left ventricular ejection fraction, left ventricular end-diastolic diameter, and N-terminal pro-brain natriuretic peptide) nor the marker of inflammation (C-reactive protein).
In this pilot study, findings on serum RIP3 supported the importance of necroptosis in HF pathomechanisms. The potential diagnostic use of circulating RIP3, unlike Drp1, as an additional biomarker of HF has also been indicated; however, further large studies are needed to prove this concept.
As cardiomyocytes have a limited capability for proliferation, renewal, and repair, the loss of heart cells followed by replacement with fibrous tissue is considered to result in the development of ...ventricular dysfunction and progression to heart failure (HF). The loss of cardiac myocytes in HF has been traditionally believed to occur mainly due to programmed apoptosis or unregulated necrosis. While extensive research work is being carried out to define the exact significance and contribution of both these cell death modalities in the development of HF, recent knowledge has indicated the existence and importance of a different form of cell death called necroptosis in the failing heart. This new cell damaging process, resembling some of the morphological features of passive necrosis as well as maladaptive autophagy, is a programmed process and is orchestrated by a complex set of proteins involving receptor-interacting protein kinase 1 and 3 (RIP1, RIP3) and mixed lineage kinase domain-like protein (MLKL). Activation of the RIP1–RIP3–MLKL signaling pathway leads to disruption of cation homeostasis, plasma membrane rupture, and finally cell death. It seems likely that inhibition of any site in this pathway may prove as an effective pharmacological intervention for preventing the necroptotic cell death in the failing heart. This review is intended to describe general aspects of the signaling pathway associated with necroptosis, to describe its relationship with cardiac dysfunction in some models of cardiac injury and discuss its potential relevance in various types of HF with respect to the underlying pathologic mechanisms.
Alternative branches of the classical renin-angiotensin-aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the ...angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.
Liver in heart failure Goncalvesová, Eva
Vnitřní lékar̆stvĭ
60, Številka:
4
Journal Article
Recenzirano
Heart failure (HF) is a syndrome with multiple organ manifestations. Liver is due to its high metabolic activity and the resulting demands on oxygenation and also due to its anatomical position close ...to the heart damaged by heart failure very often. Despite the signs of liver damage are common in heart failure, clinically significant impairment of liver function rarely occurs. Liver lesion is caused by impaired hepatic circulation in terms of congestion and/or hypoperfusion. Congestive lesion is more common. Typically manifests as painful hepatomegaly, increased direct bilirubin and alkaline phosphatase. Pure ischemic lesion is rare. It occurs in a cases with severe and prolonged liver hypoperfusion often in combination with hypoxemia and results to the sharp rise of total bilirubin and transaminase levels. Short-term prognosis of this disorder, unless the cause hypoperfusion treated successfully, is poor. Increase in bilirubin and transaminase tests as well as signs of impaired proteosynthetic liver function are associated with poor prognosis. The worst prognosis have patients with HF and current primary liver disease. Knowledge phenotypes hepatic lesions in HF is important in choosing the tactics of treatment of acute HF decompensation.
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