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
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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.
Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here, we evaluated the effect of a high-fiber diet and ...supplementation with the short-chain fatty acid acetate on the gut microbiota and the prevention of cardiovascular disease.
Gut microbiome, cardiorenal structure/function, and blood pressure were examined in sham and mineralocorticoid excess-treated mice with a control diet, high-fiber diet, or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets.
We found that high consumption of fiber modified the gut microbiota populations and increased the abundance of acetate-producing bacteria independently of mineralocorticoid excess. Both fiber and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence of
. Compared with mineralocorticoid-excess mice fed a control diet, both high-fiber diet and acetate supplementation significantly reduced systolic and diastolic blood pressures, cardiac fibrosis, and left ventricular hypertrophy. Acetate had similar effects and markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fiber and acetate were accompanied by the downregulation of cardiac and renal
, a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis, and inflammation. We also observed the upregulation of a network of genes involved in circadian rhythm in both tissues and downregulation of the renin-angiotensin system in the kidney and mitogen-activated protein kinase signaling in the heart.
A diet high in fiber led to changes in the gut microbiota that played a protective role in the development of cardiovascular disease. The favorable effects of fiber may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function.
Resuscitated cardiac arrest is associated with high mortality; however, the ability to estimate risk of adverse outcomes using existing illness severity scores is limited. Using in-hospital data ...available within the first 24 hours of admission, we aimed to develop more accurate models of risk prediction using both logistic regression (LR) and machine learning (ML) techniques, with a combination of demographic, physiologic, and biochemical information.
Patient-level data were extracted from the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database for patients who had experienced a cardiac arrest within 24 hours prior to admission to an intensive care unit (ICU) during the period January 2006 to December 2016. The primary outcome was in-hospital mortality. The models were trained and tested on a dataset (split 90:10) including age, lowest and highest physiologic variables during the first 24 hours, and key past medical history. LR and 5 ML approaches (gradient boosting machine GBM, support vector classifier SVC, random forest RF, artificial neural network ANN, and an ensemble) were compared to the APACHE III and Australian and New Zealand Risk of Death (ANZROD) predictions. In all, 39,566 patients from 186 ICUs were analysed. Mean (±SD) age was 61 ± 17 years; 65% were male. Overall in-hospital mortality was 45.5%. Models were evaluated in the test set. The APACHE III and ANZROD scores demonstrated good discrimination (area under the receiver operating characteristic curve AUROC = 0.80 95% CI 0.79-0.82 and 0.81 95% CI 0.8-0.82, respectively) and modest calibration (Brier score 0.19 for both), which was slightly improved by LR (AUROC = 0.82 95% CI 0.81-0.83, DeLong test, p < 0.001). Discrimination was significantly improved using ML models (ensemble and GBM AUROCs = 0.87 95% CI 0.86-0.88, DeLong test, p < 0.001), with an improvement in performance (Brier score reduction of 22%). Explainability models were created to assist in identifying the physiologic features that most contributed to an individual patient's survival. Key limitations include the absence of pre-hospital data and absence of external validation.
ML approaches significantly enhance predictive discrimination for mortality following cardiac arrest compared to existing illness severity scores and LR, without the use of pre-hospital data. The discriminative ability of these ML models requires validation in external cohorts to establish generalisability.
Cardiac Complications of Thoracic Irradiation Jaworski, Catherine, MBBS; Mariani, Justin A., MBBS, PhD; Wheeler, Greg, MBBS ...
Journal of the American College of Cardiology,
06/2013, Letnik:
61, Številka:
23
Journal Article
Recenzirano
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Adjuvant radiation therapy in the management of early stage breast cancer, Hodgkin’s disease, and to a lesser extent other thoracic malignancies has led to a significant improvement in ...disease-specific survival. Cardiovascular disease is now the most common nonmalignancy cause of death in radiation-treated cancer survivors, most often occurring decades after treatment. The spectrum of radiation-induced cardiac disease is broad, potentially involving any component of the heart. The relative risk of coronary artery disease, congestive heart failure, valvular heart disease, pericardial disease, conduction abnormalities, and sudden cardiac death is particularly increased. Over the years contemporary techniques have been introduced to reduce cardiac morbidity and mortality in radiation-treated cancer survivors; however, the long-term effects on the heart still remain unclear, mandating longer follow-up. Awareness and early identification of potential cardiac complications is crucial in cancer survivors, with the management often being quite complex. This review examines the epidemiology of radiation-induced cardiac disease together with its pathophysiology and explores the available treatment strategies and the potential utility of various screening strategies for affected cancer survivors.
High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with ...prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites.
One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg
·d
). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids (SCFA) produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined.
Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation.
The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
Oxygen is commonly administered to patients with ST-elevation-myocardial infarction despite previous studies suggesting a possible increase in myocardial injury as a result of coronary ...vasoconstriction and heightened oxidative stress.
We conducted a multicenter, prospective, randomized, controlled trial comparing oxygen (8 L/min) with no supplemental oxygen in patients with ST-elevation-myocardial infarction diagnosed on paramedic 12-lead ECG. Of 638 patients randomized, 441 patients had confirmed ST-elevation-myocardial infarction and underwent primary end-point analysis. The primary end point was myocardial infarct size as assessed by cardiac enzymes, troponin I, and creatine kinase. Secondary end points included recurrent myocardial infarction, cardiac arrhythmia, and myocardial infarct size assessed by cardiac magnetic resonance imaging at 6 months. Mean peak troponin was similar in the oxygen and no oxygen groups (57.4 versus 48.0 μg/L; ratio, 1.20; 95% confidence interval, 0.92-1.56; P=0.18). There was a significant increase in mean peak creatine kinase in the oxygen group compared with the no oxygen group (1948 versus 1543 U/L; means ratio, 1.27; 95% confidence interval, 1.04-1.52; P=0.01). There was an increase in the rate of recurrent myocardial infarction in the oxygen group compared with the no oxygen group (5.5% versus 0.9%; P=0.006) and an increase in frequency of cardiac arrhythmia (40.4% versus 31.4%; P=0.05). At 6 months, the oxygen group had an increase in myocardial infarct size on cardiac magnetic resonance (n=139; 20.3 versus 13.1 g; P=0.04).
Supplemental oxygen therapy in patients with ST-elevation-myocardial infarction but without hypoxia may increase early myocardial injury and was associated with larger myocardial infarct size assessed at 6 months.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01272713.
Aims
Differential microRNA expression in peripheral blood has been observed in patients with heart failure, suggesting their value as potential biomarkers and likely contributors to disease ...mechanisms. In the present study, we aimed to evaluate the transcardiac gradient of 84 cardio‐microRNAs in healthy and failing hearts to determine which microRNAs are released or absorbed by the myocardium in heart failure.
Methods and results
Eight healthy volunteers and nine patients with congestive heart failure were included. Arterial and coronary sinus blood samples were collected, and microRNAs were extracted. The expression of microRNAs was analysed using real‐time PCR by the miScript miRNA PCR Array Human Cardiovascular Disease. In coronary sinus samples, the microRNAs miR‐16‐5p, miR‐27a‐3p, miR‐27b‐3p, miR‐29b‐3p, miR‐29c‐3p, miR‐30e‐5p, miR‐92a‐3p, miR‐125b‐5p, miR‐140‐5p, miR‐195‐5p, miR‐424‐5p, and miR‐451a were significantly down‐regulated, and let‐7a‐5p, let‐7c‐5p, let‐7e‐5p, miR‐23b‐3p, miR‐107, miR‐155‐5p, miR‐181a‐5p, miR‐181b‐5p and miR‐320a were up‐regulated in heart failure. Left ventricular filling pressure was negatively correlated with miR‐195, miR‐16, miR‐29b‐3p, miR‐29c‐3p, miR‐451a, and miR‐92a‐3p. The failing heart released let‐7b‐5p, let‐7c‐5p, let‐7e‐5p, miR‐122‐5p, and miR‐21‐5p, and absorbed miR‐16‐5p, miR‐17‐5p, miR‐27a‐3p, miR‐30a‐5p, miR‐30d‐5p, miR‐30e‐5p, miR‐130a‐3p, miR‐140‐5p, miR‐199a‐5p, and miR‐451a. In silico analyses suggest that the transcardiac gradient of microRNAs in heart failure may target pathways related to heart disease.
Conclusion
We determined the transcardiac gradient of cardio‐microRNAs in failing hearts, which supports the use of these microRNAs as potential biomarkers. The microRNAs described here may have a role in the pathophysiology of heart failure as they might be involved in pathways related to disease progression, including fibrosis.
Summary Background Heart failure with preserved ejection fraction (HFPEF) is a common, globally recognised, form of heart failure for which no treatment has yet been shown to improve symptoms or ...prognosis. The pathophysiology of HFPEF is complex but characterised by increased left atrial pressure, especially during exertion, which might be a key therapeutic target. The rationale for the present study was that a mechanical approach to reducing left atrial pressure might be effective in HFPEF. Methods The REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) study was an open-label, single-arm, phase 1 study designed to assess the performance and safety of a transcatheter interatrial shunt device (IASD, Corvia Medical, Tewkesbury, MA, USA) in patients older than 40 years of age with symptoms of HFPEF despite pharmacological therapy, left ventricular ejection fraction higher than 40%, and a raised pulmonary capillary wedge pressure at rest (>15 mm Hg) or during exercise (>25 mm Hg). The study was done at 21 centres (all departments of cardiology in the UK, Netherlands, Belgium, France, Germany, Austria, Denmark, Australia, and New Zealand). The co-primary endpoints were the safety and performance of the IASD at 6 months, together with measures of clinical efficacy, including functional capacity and clinical status, analysed per protocol. This study is registered with ClinicalTrials.gov , number NCT01913613. Findings Between Feb 8, 2014, and June 10, 2015, 68 eligible patients were entered into the study. IASD placement was successful in 64 patients and seemed to be safe and well tolerated; no patient had a peri-procedural or major adverse cardiac or cerebrovascular event or need for cardiac surgical intervention for device-related complications during 6 months of follow-up. At 6 months, 31 (52%) of 60 patients had a reduction in pulmonary capillary wedge pressure at rest, 34 (58%) of 59 had a lower pulmonary capillary wedge pressure during exertion, and 23 (39%) of 59 fulfilled both these criteria. Mean exercise pulmonary capillary wedge pressure was lower at 6 months than at baseline, both at 20 watts workload (mean 32 mm Hg SD 8 at baseline vs 29 mm Hg 9 at 6 months, p=0·0124) and at peak exercise (34 mm Hg 8 vs 32 8, p=0·0255), despite increased mean exercise duration (baseline vs 6 months: 7·3 min SD 3·1 vs 8·2 min 3·4, p=0·03). Sustained device patency at 6 months was confirmed by left-to-right shunting (pulmonary/systemic flow ratio: 1·06 SD 0·32 at baseline vs 1·27 0·20 at 6 months, p=0·0004). Interpretation Implantation of an interatrial shunt device is feasible, seems to be safe, reduces left atrial pressure during exercise, and could be a new strategy for the management of HFPEF. The effectiveness of IASD compared with existing treatment for patients with HFPEF requires validation in a randomised controlled trial. Funding Corvia Medical Inc.
Heart failure (HF) is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation ...may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice) or type II diabetes (Israeli Sand-rats) and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow) to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.
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