Right ventricular dysfunction in patients with new-onset heart failure: longitudinal follow-up during guideline-directed medical therapy.

AIMS: Improvement in left ventricular ejection fraction (LVEF) after up-titration of guideline-directed medical therapy (GDMT) has been well described in heart failure (HF) patients. Less is known about the prevalence and clinical course of right ventricular dysfunction (RVD) in patients with new-onset HF. METHODS AND RESULTS: From 2012 to 2018, 625 patients with a recent (<3 months) diagnosis of HF were referred to a specialized nurse-led HF clinic for protocolized up-titration of GDMT. RVD, defined as tricuspid annular plane systolic excursion (TAPSE) <17 mm, was assessed at baseline and at the follow-up visit. Patients were followed for the combined endpoint of all-cause mortality and HF hospitalization for a mean of 3.3 ± 1.9 years. Of the 625 patients, 241 (38.6%) patients had RVD at baseline. Patients with RVD were older, more symptomatic, had a lower LVEF, and more often had a history of cardiothoracic surgery and atrial fibrillation. After a median follow-up of 9 months, right ventricular function normalized in 49% of the patients with baseline RVD. RVD at baseline was associated with a higher risk of the combined endpoint (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.21-2.18). Right ventricular function normalization was associated with a lower risk for the combined endpoint (HR 0.56, 95% CI 0.31-0.99), independent of baseline TAPSE, age, sex, and LVEF. CONCLUSION: More than one-third of patients with new-onset HF have RVD. RVD is associated with a higher risk of all-cause mortality and HF hospitalization. Recovery of RVD regularly occurs during up-titration of GDMT and is associated with improved clinical outcomes.

Left atrial structure and function in heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF): systematic review and meta-analysis.

Left atrial (LA) structure and function in heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF) is only established in small studies. Therefore, we conducted a systematic review of LA structure and function in order to find differences between patients with HFrEF and HFpEF. English literature on LA structure and function using echocardiography was reviewed to calculate pooled prevalence and weighted mean differences (WMD). A total of 61 studies, comprising 8806 patients with HFrEF and 9928 patients with HFpEF, were included. The pooled prevalence of atrial fibrillation (AF) was 34.4% versus 42.8% in the acute inpatient setting, and 20.1% versus 33.1% in the chronic outpatient setting when comparing between HFrEF and HFpEF. LA volume index (LAVi), LA reservoir global longitudinal strain (LAGLSR), and E/e' was 59.7 versus 52.7 ml/m2, 9.0% versus 18.9%, and 18.5 versus 14.0 in the acute inpatient setting, and 48.3 versus 38.2 ml/m2, 12.8% versus 23.4%, and 16.9 versus 13.5 in the chronic outpatient setting when comparing HFrEF versus HFpEF, respectively. The relationship between LAVi and LAGLSR was significant in HFpEF, but not in HFrEF. Also, in those studies that directly compared patients with HFrEF versus HFpEF, those with HFrEF had worse LAGLSR [WMD = 16.3% (22.05,8.61); p < 0.001], and higher E/e' [WMD = -0.40 (-0.56, -0.24); p < 0.05], while LAVi was comparable. When focusing on acute hospitalized patients, E/e' was comparable between patients with HFrEF and HFpEF. Despite the higher burden of AF in HFpEF, patients with HFrEF had worse LA global function. Left atrial myopathy is not specifically related to HFpEF.

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure.

AIMS: Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non-ischaemic HF, it is important to better understand differences in underlying molecular mechanisms. METHODS AND RESULTS: We performed a biological physical protein-protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT-CHF study, 715 of whom had ischaemic HF and 445 had non-ischaemic HF. Second, we constructed an enriched physical protein-protein interaction network, followed by a pathway over-representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non-ischaemic HF patients. We found 21/92 proteins to be up-regulated and 2/92 down-regulated in ischaemic relative to non-ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin-like growth factor binding protein-1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort. CONCLUSIONS: Pathophysiological pathways distinguishing patients with ischaemic HF from those with non-ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF.

Concentric vs. eccentric remodelling in heart failure with reduced ejection fraction: clinical characteristics, pathophysiology and response to treatment.

AIMS: Heart failure is traditionally classified by left ventricular ejection fraction (LVEF), rather than by left ventricular (LV) geometry, with guideline-recommended therapies in heart failure with reduced ejection fraction (HFrEF) but not heart failure with preserved ejection fraction (HFpEF). Most patients with HFrEF have eccentric LV hypertrophy, but some have concentric LV hypertrophy. We aimed to compare clinical characteristics, biomarker patterns, and response to treatment of patients with HFrEF and eccentric vs. concentric LV hypertrophy. METHODS AND RESULTS: We performed a retrospective post-hoc analysis including 1015 patients with HFrEF (LVEF <40%) from the multinational observational BIOSTAT-CHF study. LV geometry was classified using two-dimensional echocardiography. Network analysis of 92 biomarkers was used to investigate pathophysiologic pathways. Concentric LV hypertrophy was present in 142 (14%) patients, who were on average older and more likely hypertensive compared to those with eccentric LV hypertrophy. Network analysis revealed that N-terminal pro-B-type natriuretic peptide was an important hub in eccentric hypertrophy, whereas in concentric hypertrophy, tumour necrosis factor receptor 1, urokinase plasminogen activator surface receptor, paraoxonase and P-selectin were central hubs. Up-titration of beta-blockers was associated with a mortality benefit in HFrEF with eccentric but not concentric LV hypertrophy (P-value for interaction ≤0.001). For angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, the hazard ratio for mortality was higher in concentric hypertrophy, but the interaction was not significant. CONCLUSION: Patients with HFrEF with concentric hypertrophy have a clinical and biomarker phenotype that is distinctly different from those with eccentric hypertrophy. Patients with concentric hypertrophy may not experience similar benefit from up.-titration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers compared to patients with eccentric hypertrophy.

Cardiac Function After Radiation Therapy for Breast Cancer.

PURPOSE: The main purpose of this study was to test the hypothesis that incidental cardiac irradiation is associated with changes in cardiac function in breast cancer (BC) survivors treated with radiation therapy (RT). METHODS AND MATERIALS: We conducted a cross-sectional study consisting of 109 BC survivors treated with RT between 2005 and 2011. The endpoint was cardiac function, assessed by echocardiography. Systolic function was assessed with the left ventricular ejection fraction (LVEF) (n = 107) and the global longitudinal strain (GLS) of the left ventricle (LV) (n = 52). LV diastolic dysfunction (n = 109) was defined by e' at the lateral and septal region, which represents the relaxation velocity of the myocardium. The individual calculated RT dose parameters of the LV and coronary arteries were collected from 3-dimensional computed tomography-based planning data. Univariable and multivariable analysis using forward selection was performed to identify the best predictors of cardiac function. Robustness of selection was assessed using bootstrapping. The resulting multivariable linear regression model was presented for the endpoints of systolic and diastolic function. RESULTS: The median time between BC diagnosis and echocardiography was 7 years. No relation between RT dose parameters and LVEF was found. In the multivariable analysis for the endpoint GLS of the LV, the maximum dose to the left main coronary artery was most often selected across bootstrap samples. For decreased diastolic function, the most often selected model across bootstrap samples included age at time of BC diagnosis and hypertension at baseline. Cardiac dose-volume histogram parameters were less frequently selected for this endpoint. CONCLUSIONS: This study shows an association between individual cardiac dose distributions and GLS of the LV after RT for BC. No relation between RT dose parameters and LVEF was found. Diastolic function was most associated with age and hypertension at time of BC diagnosis. Further research is needed to make definitive conclusions.

Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction.

BACKGROUND: Comorbidities play a major role in heart failure. Whether prevalence and prognostic importance of comorbidities differ between heart failure with preserved ejection fraction (HFpEF), mid-range (HFmrEF) or reduced ejection fraction (HFrEF) is unknown. METHODS: Patients from index (n = 2516) and validation cohort (n = 1738) of The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) were pooled. Eight non-cardiac comorbidities were assessed; diabetes mellitus, thyroid dysfunction, obesity, anaemia, chronic kidney disease (CKD, estimated glomerular filtration rate < 60 mL/min/1.73 m2), COPD, stroke and peripheral arterial disease. Patients were classified based on ejection fraction. The association of each comorbidity with quality of life (QoL), all-cause mortality and hospitalisation was evaluated. RESULTS: Patients with complete comorbidity data were included (n = 3499). Most prevalent comorbidity was CKD (50%). All comorbidities showed the highest prevalence in HFpEF, except for stroke. Prevalences of HFmrEF were in between the other entities. COPD was the comorbidity associated with the greatest reduction in QoL. In HFrEF, almost all were associated with a significant reduction in QoL, while in HFpEF only CKD and obesity were associated with a reduction. Most comorbidities in HFrEF were associated with an increased mortality risk, while in HFpEF only CKD, anaemia and COPD were associated with higher mortality risks. CONCLUSIONS: The highest prevalence of comorbidities was seen in patients with HFpEF. Overall, comorbidities were associated with a lower QoL, but this was more pronounced in patients with HFrEF. Most comorbidities were associated with higher mortality risks, although the associations with diabetes were only present in patients with HFrEF.

Correlation with invasive left ventricular filling pressures and prognostic relevance of the echocardiographic diastolic parameters used in the 2016 ESC heart failure guidelines and in the 2016 ASE/EACVI recommendations: a systematic review in patients with heart failure with preserved ejection fraction.

AIMS: Five echocardiographic parameters-left atrial volume index, left ventricular mass index, tricuspid regurgitation velocity, myocardial tissue velocity, and the ratio of early mitral inflow to tissue velocity of the mitral annulus (E/e')-are recommended in both the current European Society of Cardiology heart failure guidelines and the American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations for the evaluation of left ventricular diastolic function. We aimed to perform a systematic review of these echocardiographic parameters at resting conditions for their correlation with left ventricular filling pressures in patients with heart failure with preserved ejection fraction (HFpEF). In addition, the prognostic value of these parameters was assessed. METHODS AND RESULTS: Nine studies reported the correlation between echocardiography and invasive haemodynamics, and 18 papers reported on the prognostic value of echocardiography in HFpEF. Among the parameters, most data were reported for E/e'. The pooled correlation coefficient r was 0.56 for the relation between E/e' and invasively measured filling pressures. Combined weighted-mean meta-analysis of prognostic studies resulted in a hazard ratio of 1.05 (95% confidence interval 1.03-1.06) per unit increase in E/e' for the combined outcome of all-cause mortality and cardiovascular hospitalization. The other echocardiographic parameters, when taken individually, had similar or lower association with prognosis. CONCLUSION: Only a small number of studies validated the use of echocardiographic parameters at rest in patients with HFpEF. The best established parameter appears to be E/e', but the existing data only show modest correlations of E/e' with invasive filling pressures and outcomes in HFpEF.

What have we learned about heart failure with mid-range ejection fraction one year after its introduction?

The 2016 European Society of Cardiology heart failure guidelines introduced the term 'heart failure with mid-range ejection fraction' (HFmrEF) to refer to patients with heart failure and a mildly reduced ejection fraction of 40-49%. About 20% of heart failure patients fall in this category. One of the main reasons for the introduction of this category was to stimulate research into this grey area. This review aims to highlight the key findings that have been published so far. Firstly, HFmrEF more closely resembles heart failure with reduced (HFrEF) than preserved ejection fraction (HFpEF) with regard to ischaemic aetiology, which is more frequent in both HFmrEF and HFrEF compared to HFpEF. Secondly, changes in ejection fraction over time are common, and seem to be more important than baseline ejection fraction alone. Patients who progress from HFmrEF to HFrEF have a worse prognosis than those who remain stable or transition to HFpEF. Lastly, and perhaps most importantly, retrospective analyses from a randomized trial suggest that patients with HFmrEF seem to benefit from therapies that have shown to improve outcome in HFrEF, whereas no such benefit was seen in patients with HFpEF.