Advances in cardiovascular research have identified oxidative stress as an important pathophysiological pathway in the development and progression of heart failure. Oxidative stress is defined as the ...imbalance between the production of reactive oxygen species (ROS) and the endogenous antioxidant defence system. Under physiological conditions, small quantities of ROS are produced intracellularly, which function in cell signalling, and can be readily reduced by the antioxidant defence system. However, under pathophysiological conditions, the production of ROS exceeds the buffering capacity of the antioxidant defence system, resulting in cell damage and death. Over the last decades several studies have tried to target oxidative stress with the aim to improve outcome in patients with heart failure, with very limited success. The reasons as to why these studies failed to demonstrate any beneficial effects remain unclear. However, one plausible explanation might be that currently employed strategies, which target oxidative stress by exogenous inhibition of ROS production or supplementation of exogenous antioxidants, are not effective enough, while bolstering the endogenous antioxidant capacity might be a far more potent avenue for therapeutic intervention. In this review, we provide an overview of oxidative stress in the pathophysiology of heart failure and the strategies utilized to date to target this pathway. We provide novel insights into modulation of endogenous antioxidants, which may lead to novel therapeutic strategies to improve outcome in patients with heart failure.
Sex differences in heart failure Lam, Carolyn S P; Arnott, Clare; Beale, Anna L ...
European heart journal,
12/2019, Letnik:
40, Številka:
47
Journal Article
Recenzirano
Odprti dostop
Abstract
The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and ...under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20–25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.
There is a paucity of evidence for dose and pace of up-titration of guideline-directed medical therapies after admission to hospital for acute heart failure.
In this multinational, open-label, ...randomised, parallel-group trial (STRONG-HF), patients aged 18–85 years admitted to hospital with acute heart failure, not treated with full doses of guideline-directed drug treatment, were recruited from 87 hospitals in 14 countries. Before discharge, eligible patients were randomly assigned (1:1), stratified by left ventricular ejection fraction (≤40% vs >40%) and country, with blocks of size 30 within strata and randomly ordered sub-blocks of 2, 4, and 6, to either usual care or high-intensity care. Usual care followed usual local practice, and high-intensity care involved the up-titration of treatments to 100% of recommended doses within 2 weeks of discharge and four scheduled outpatient visits over the 2 months after discharge that closely monitored clinical status, laboratory values, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations. The primary endpoint was 180-day readmission to hospital due to heart failure or all-cause death. Efficacy and safety were assessed in the intention-to-treat (ITT) population (ie, all patients validly randomly assigned to treatment). The primary endpoint was assessed in all patients enrolled at hospitals that followed up patients to day 180. Because of a protocol amendment to the primary endpoint, the results of patients enrolled on or before this amendment were down-weighted. This study is registered with ClinicalTrials.gov, NCT03412201, and is now complete.
Between May 10, 2018, and Sept 23, 2022, 1641 patients were screened and 1078 were successfully randomly assigned to high-intensity care (n=542) or usual care (n=536; ITT population). Mean age was 63·0 years (SD 13·6), 416 (39%) of 1078 patients were female, 662 (61%) were male, 832 (77%) were White or Caucasian, 230 (21%) were Black, 12 (1%) were other races, one (<1%) was Native American, and one (<1%) was Pacific Islander (two <1% had missing data on race). The study was stopped early per the data and safety monitoring board's recommendation because of greater than expected between-group differences. As of data cutoff (Oct 13, 2022), by day 90, a higher proportion of patients in the high-intensity care group had been up-titrated to full doses of prescribed drugs (renin-angiotensin blockers 278 55% of 505 vs 11 2% of 497; β blockers 249 49% vs 20 4%; and mineralocorticoid receptor antagonists 423 84% vs 231 46%). By day 90, blood pressure, pulse, New York Heart Association class, bodyweight, and NT-proBNP concentration had decreased more in the high-intensity care group than in the usual care group. Heart failure readmission or all-cause death up to day 180 occurred in 74 (15·2% down-weighted adjusted Kaplan-Meier estimate) of 506 patients in the high-intensity care group and 109 (23·3%) of 502 patients in the usual care group (adjusted risk difference 8·1% 95% CI 2·9–13·2; p=0·0021; risk ratio 0·66 95% CI 0·50–0·86). More adverse events by 90 days occurred in the high-intensity care group (223 41% of 542) than in the usual care group (158 29% of 536) but similar incidences of serious adverse events (88 16% vs 92 17%) and fatal adverse events (25 5% vs 32 6%) were reported in each group.
An intensive treatment strategy of rapid up-titration of guideline-directed medication and close follow-up after an acute heart failure admission was readily accepted by patients because it reduced symptoms, improved quality of life, and reduced the risk of 180-day all-cause death or heart failure readmission compared with usual care.
Roche Diagnostics.
The European Society of Cardiology (ESC) has published a series of guidelines on heart failure (HF) over the last 25 years, most recently in 2016. Given the amount of new information that has become ...available since then, the Heart Failure Association (HFA) of the ESC recognized the need to review and summarise recent developments in a consensus document. Here we report from the HFA workshop that was held in January 2019 in Frankfurt, Germany. This expert consensus report is neither a guideline update nor a position statement, but rather a summary and consensus view in the form of consensus recommendations. The report describes how these guidance statements are supported by evidence, it makes some practical comments, and it highlights new research areas and how progress might change the clinical management of HF. We have avoided re‐interpretation of information already considered in the 2016 ESC/HFA guidelines.
Specific new recommendations have been made based on the evidence from major trials published since 2016, including sodium–glucose co‐transporter 2 inhibitors in type 2 diabetes mellitus, MitraClip for functional mitral regurgitation, atrial fibrillation ablation in HF, tafamidis in cardiac transthyretin amyloidosis, rivaroxaban in HF, implantable cardioverter‐defibrillators in non‐ischaemic HF, and telemedicine for HF. In addition, new trial evidence from smaller trials and updated meta‐analyses have given us the chance to provide refined recommendations in selected other areas.
Further, new trial evidence is due in many of these areas and others over the next 2 years, in time for the planned 2021 ESC guidelines on the diagnosis and treatment of acute and chronic heart failure.
Congestion is the main reason for hospitalization in patients with acute decompensated heart failure and is an important target for therapy. However, achieving complete decongestion can be ...challenging. Furthermore, residual congestion before discharge from hospital is associated with a high risk of early rehospitalization and death. An improved understanding of the pathophysiology of congestion is of great importance in finding better and more personalized therapies. In this Review, we describe the two different forms of congestion - intravascular congestion and tissue congestion - and hypothesize that differentiating between and specifically treating these two different forms of congestion could improve the outcomes of patients with acute decompensated heart failure. Although the majority of these patients have a combination of both intravascular and tissue congestion, one phenotype can dominate. Each of these two forms of congestion has a different pathophysiology and requires a different diagnostic approach. We provide an overview of novel and established biomarkers, imaging modalities and mechanical techniques for identifying each type of congestion. Treatment with loop diuretics, the current cornerstone of decongestive treatment, reduces circulating blood volume and thereby reduces intravascular congestion. However, the osmolality of the circulating blood decreases with the use of loop diuretics, which might result in less immediate translocation of fluid from the tissues (lungs, abdomen and periphery) to the circulation when the plasma refill rate is exceeded. By contrast, aquaretic drugs (such as vasopressin antagonists) predominantly cause water excretion, which increases the osmolality of the circulating blood, potentially improving translocation of fluid from the tissues to the circulation and thereby relieving tissue congestion.
Background Iron deficiency (ID) is an emerging problem in patients with chronic heart failure (HF) and can be a potential therapeutic target. However, not much is known about the prevalence, ...predictors, and prognosis of ID in patients with chronic HF. Methods In an international pooled cohort comprising 1,506 patients with chronic HF, we studied the clinical associates of ID and its prognostic consequences. Results Iron deficiency (defined as a ferritin level <100 μg/L or ferritin 100-299 μg/L with a transferrin saturation <20%) was present in 753 patients (50%). Anemic patients were more often iron deficient than nonanemic patients (61.2% vs 45.6%, P < .001). Other independent predictors of ID were higher New York Heart Association class, higher N-terminal pro-brain-type natriuretic peptide levels, lower mean corpuscular volume levels, and female sex (all P < .05). During follow-up (median 1.92 years, interquartile range 1.18-3.26 years), 440 patients died (29.2%). Kaplan-Meier survival analysis revealed ID as a strong predictor for mortality (log rank χ2 10.2, P = .001). In multivariable hazard models, ID (but not anemia) remained a strong and independent predictor of mortality (hazard ratio 1.42, 95% confidence interval 1.14-1.77, P = .002). Finally, the presence of ID significantly enhanced risk classification and integrated discrimination improvement when added to a prediction model with established risk factors. Conclusions Iron deficiency is common in patients with chronic HF, relates to disease severity, and is a strong and independent predictor of outcome. In this study, ID appears to have greater predictive power than anemia.
MicroRNAs (miRNAs) are increasingly recognized to play important roles in cardiovascular diseases, including heart failure. These small, non‐coding RNAs have been identified in tissue and are ...involved in several pathophysiological processes related to heart failure, such as cardiac fibrosis and hypertrophy. As a result, miRNAs have become interesting novel drug targets, leading to the development of miRNA mimics and antimirs. MicroRNAs are also detected in the circulation, and are proposed as potential diagnostic and prognostic biomarkers in heart failure. However, their role and function in the circulation remains to be resolved. Here, we review the potential roles of miRNAs as circulating biomarkers and as targets for therapy.