Prognostication in heart failure across ejection fraction phenotypes and challenging subgroups : data from the Swedish heart failure registry

Background. The growing prevalence of heart failure (HF) worldwide determines an increasing burden on healthcare systems. HF phenotypes differ for several patient characteristics. Treatments with proven efficacy are mainly available for HF with reduced ejection fraction (HFrEF), whereas for HF with mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction evidence on treatment effect is more recent and limited to a single randomized control trial (RCT) and post-hoc/subgroup analyses of former RCTs. Although therapies affect survival in HFrEF, treatment implementation remains poor in particular in specific and more challenging subgroups. Aims. The overall purpose is to provide a thorough characterization in terms of prognostication, to explore associations with outcomes and reasons for underuse of HF treatments while focusing on challenging settings underrepresented in RCTs and the different HF phenotypes (HFrEF, HFpEF and HFmrEF). Specific aims are: • to assess gender-related differences in clinical characteristics, therapeutic strategies and outcomes in order to characterize the specific features of women affected by HF across the HF phenotypes (study I) • to evaluate the use and the predictors of use of betablockers in older HFrEF patients, and the association between betablocker therapy and outcomes (study II) • to assess the state of implementation of evidence-based treatments for HFrEF in older patients (study III) • to explore the burden of HF on an healthcare system, with particular attention to the impact of the increasing burden of comorbidities on cardiovascular (CV) and non-CV mortality and morbidity (study IV) These specific aims are assessed in a large and unselected contemporary cohort of HF patients, such as the Swedish HF Registry (SwedeHF). Sex-based differences in heart failure across the ejection fraction spectrum: Phenotyping, and prognostic and therapeutic implications. In the SwedeHF Registry population, of 42,987 patients, 37% were females (55% with HFpEF, 39% with HFmrEF, 29% with HFrEF). Females were older, had more symptoms and more likely hypertension and kidney disease. There were differences in treatment use, with higher rates of beta-blocker and digoxin use in women vs men. Females less likely received HF devices. Adjusted risk of mortality/HF hospitalization was lower in females regardless of EF. The observed sex-related differences suggest to implement strategies for higher recruitment of women in RCTs. Association between beta-blocker use and mortality/morbidity in older patients with heart failure with reduced ejection fraction: A propensity score-matched analysis from the Swedish Heart Failure Registry. We assessed the association between beta-blocker use, all-cause mortality and CV mortality/HF hospitalization in a 1:1 propensity score-matched cohort of patients with HFrEF and aged ≥80 years. Of 6562 patients aged ≥80 years, 5640 (86%) received beta-blocker. In the matched cohort (n=1732) beta-blocker use was associated lower risk of all-cause mortality. There was no signifantly lower risk of CV mortality/HF with vs. without beta-blocker in the matched cohort due to the lack of association between beta-blocker use and the outcome HF hospitalization. However, after adjustment rather than matching for the propensity score in the overall cohort, beta-blocker use was associated with reduced risk of all-cause mortality and CV mortality/HF hospitalization. Use of evidence-based therapy in heart failure with reduced ejection fraction across age strata. We studied 27430 patients with HFrEF: 31% were <70, 34% 70-79 and 35% ≥80 years old. Use of renin-angiotensin-system/angiotensin receptor neprilysin inhibitors, beta-blockers and mineralocorticoid receptor antagonists progressively decreased with increasing age. Older patients were less likely treated with target doses of or combinations of HF medications. Except that for cardiac resynchronization therapy, after extensive adjustments age was inversely associated with the probability of guideline-directed medical therapy (GDMT) use and target dose achievement. Persistent high burden of heart failure across the ejection fraction spectrum in a nationwide setting. A total of 76510 HF patients (53% HFrEF, had reduced EF 23% HFmrEF, 24% HFpEF) from the SwedeHF Registry were compared 1:3 with a sex, age, and county matched non-HF population. The incidence of cardiovascular and non-cardiovascular mortality/morbidity outcomes, as well as the in-hospital length of stay, was up to 5 times higher in HF vs non-HF patients. Across the EF spectrum, HFrEF was more exposed to HF hospitalization, whereas HFpEF to all-cause and non-cardiovascular hospitalization and mortality. Conclusions. In the overall management of patients with HF, there are challenging subgroups that remain underexplored and frequently under-represented in RCT. Weaker evidence supporting the use of treatments and clinical inertia lead to lower adherence to current therapeutic recommendations. In our study women presented peculiarities in characteristics and treatments across the whole EF spectrum compared with men, with better survival/ morbidity after adjustment for other patient characteristics. Patients in the older age range represent another group with a great representation in the overall real-world HF population, but often poorly considered and represented in clinical trials and by the scientific community in terms of treatment use implementation. Concerns regarding lower or no efficacy of treatments in older groups are not supported by post-hoc analyses of RCTs, and we observed a convincing lower mortality/morbidity risk associated with beta-blockers treatment in HFrEF over 80 years old, without any safety concerns. Despite the available data support evidencebased treatments regardless of age, in our cohort study we demonstrated that, with the exception of cardiac resynchronization therapy, medical treatments and devices are largely under-used and under-dosed in older patients with HFrEF. Finally, the increasing complexity of the contemporary HF population, partially given by the growing age and the increasing number of comorbidities, heavily burdens on the whole healthcare system, with HF patients experiencing a dramatically higher rate of cardiovascular and non-cardiovascular mortality/ morbidity events. This claims for further efforts in the optimization of resources allocation and design of future RCTs

Use of Renin–Angiotensin–Aldosterone System Inhibitors in Older Patients with Heart Failure and Reduced Ejection Fraction

Patients enrolled in randomised clinical trials may not be representative of the real-world population of people with heart failure (HF). Older patients are frequently excluded and this limits the strength of evidence which supports the use of specific HF treatments in this patient group. Lack of evidence together with fear of adverse effects, drug interactions and lower tolerance may lead to the undertreatment of older patients and a less favourable outcome. Renin–angiotensin–aldosterone system (RAAS) inhibitors are the cornerstone of treatment for patients with HF with reduced ejection fraction (HFrEF), but despite the class I recommendation for all patients regardless of age in the guidelines, there are signs that RAAS inhibitors are underused among older patients. Large registry- based studies suggest that RAAS inhibitors may be at least as effective in older patients as younger ones, but these findings need to be confirmed by randomised clinical trials

Evidence-based Therapy in Older Patients with Heart Failure with Reduced Ejection Fraction

Older patients are becoming prevalent among people with heart failure (HF) as the overall population ages. However, older patients are largely under-represented, or even excluded, from randomised controlled trials on HF with reduced ejection fraction, limiting the generalisability of trial results in the real world and leading to weaker evidence supporting the use and titration of guideline-directed medical therapy (GDMT) in older patients with HF with reduced ejection fraction. This, in combination with other factors limiting the application of guideline recommendations, including a fear of poor tolerability or adverse effects, the heavy burden of comorbidities and the need for multiple therapies, classically leads to lower adherence to GDMT in older patients. Although there are no data supporting the under-use and under-dosing of HF medications in older patients, large registry-based studies have confirmed age as one of the major obstacles to treatment optimisation. In this review, the authors provide an overview of the contemporary state of implementation of GDMT in older groups and the reasons for the lower use of treatments, and discuss some measures that may help improve adherence to evidence-based recommendations in older age groups

415 Correlation between tissue abnormalities and myocardial deformation indices in arrhythmogenic cardiomyopathy: a pilot study

Abstract Aims To evaluate the correlation between cardiac magnetic resonance (CMR) tissue abnormalities and impairment of myocardial deformation indices in patients with definite diagnosis of arrhythmogenic cardiomyopathy (AC). Methods and results 41 AC Patients with available CMR study were enrolled. Myocardial deformation indices (i.e. global longitudinal strain -GLS-; global circumferential strain -GCS-; global radial strain -GRS-) for both ventricles were calculated using feature tracking analysis. Quantification of tissue abnormalities (i.e. late gadolinium enhancement -LGE- extension expressed as percentage of total ventricular mass) was performed. Spearman's rho correlation was evaluated. Mean age was 44 ± 13 years and 26 (63%) patients were male. Mean left ventricular (LV) ejection fraction (EF) was 54 ± 10% and mean right ventricular (RV) EF was 49 ± 12%. Median LV LGE extension was 8.9% (1.05–21) and median RV LGE extension was 0 (0–6.92). All myocardial deformation indices were moderately associated with LGE extension (for LV 3D GLS Spearman's Rho 0.423, P 0.016; 2D GCS Spearman's Rho 0.388, P 0.028; 3D GCS 0.362, P 0.042; 2D GRS Spearman's Rho −0.417, P 0.018; 3D GRS −0.396, P 0.025; for RV 2D GLS Spearman's Rho 0.385, P 0.030; RV GCS Spearman's Rho 0.450, P 0.010; RV GRS Spearman's Rho −0.459, P 0.008). Conclusions All myocardial deformation indices showed a moderate association with LGE extension in a cohort of patients with definite AC. Further studies are needed to validate this observation and understand its implications

Persistent High Burden of Heart Failure Across the Ejection Fraction Spectrum in a Nationwide Setting

Background Heart failure (HF) has a dramatic impact on worldwide health care systems that is determined by the growing prevalence of and the high exposure to cardiovascular and noncardiovascular events. Prognosis remains poor. We sought to compare a large population with HF across the ejection fraction (EF) spectrum with a population without HF for patient characteristics, and HF, cardiovascular, and noncardiovascular outcomes. Methods and Results Patients with HF registered in the Swedish HF registry in 2005 to 2018 were compared 1:3 with a sex-, age-, and county-matched population without HF. Outcomes were cardiovascular and noncardiovascular mortality and hospitalizations. Of 76 453 patients with HF, 53% had reduced EF, 23% mildly reduced EF, and 24% preserved EF. Compared with those without HF, patients with HF had more cardiovascular and noncardiovascular comorbidities and worse socioeconomic status. Incidence of cardiovascular and noncardiovascular events was higher in people with HF versus non-HF, with increased risk of all-cause (hazard ratio [HR], 2.53 [95% CI, 2.50-2.56]), cardiovascular (HR, 4.67 [95% CI, 4.59-4.76]), and noncardiovascular (HR, 1.49 [95% CI, 1.46-1.52]) mortality, 2- to 5-fold higher risk of first/repeated cardiovascular and noncardiovascular hospitalizations, and ~4 times longer in-hospital length of stay for any cause. Patients with HF with reduced EF had higher risk of HF hospitalizations, whereas those with HF with preserved EF had higher risk of all-cause and noncardiovascular hospitalization and mortality. Conclusions Patients with HF exert a high health care burden, with a much higher risk of cardiovascular, all-cause, and noncardiovascular events, and nearly 4 times as many days spent in hospital compared with those without HF. These epidemiological data may enable strategies for optimal resource allocation and HF trial design

Persistent recovery of normal left ventricular function and dimension in idiopathic dilated cardiomyopathy during long\u2010term follow\u2010up: does real healing exist?

BACKGROUND: An important number of patients with idiopathic dilated cardiomyopathy have dramatically improved left ventricular function with optimal treatment; however, little is known about the evolution and long-term outcome of this subgroup, which shows apparent healing. This study assesses whether real healing actually exists in dilated cardiomyopathy. METHODS AND RESULTS: Persistent apparent healing was evaluated among 408 patients with dilated cardiomyopathy receiving tailored medical treatment and followed over the very long-term. Persistent apparent healing was defined as left ventricular ejection fraction 6550% and indexed left ventricular end-diastolic diameter 6433 mm/m(2) at both mid-term (19\ub14 months) and long-term (103\ub19 months) follow-up. At mid-term, 63 of 408 patients (15%) were apparently healed; 38 (60%; 9%of the whole population) showed persistent apparent healing at long-term evaluation. No predictors of persistent apparent healing were found. Patients with persistent apparent healing showed better heart transplant\u2013free survival at very long-term follow-up (95% versus 71%; P=0.014) compared with nonpersistently normalized patients. Nevertheless, in the very longterm, 37% of this subgroup experienced deterioration of left ventricular systolic function, and 5% died or had heart transplantation. CONCLUSIONS: Persistent long-term apparent healing was evident in a remarkable proportion of dilated cardiomyopathy patients receiving optimal medical treatment and was associated with stable normalization of main clinical and laboratory features. This condition can be characterized by a decline of left ventricular function over the very long term, highlighting the relevance of serial nd individualized follow-up in all patients with dilated cardiomyopathy, especially considering the absence of predictors for longterm apparent healing

Transient versus persistent improved ejection fraction in non-ischaemic dilated cardiomyopathy

Aims The recent definition of heart failure with improved ejection fraction outlined the importance of the longitudinal assessment of left ventricular ejection fraction (LVEF). However, long-term progression and outcomes of this subgroup are poorly explored. We sought to assess the LVEF trajectories and their correlations with outcome in non-ischaemic dilated cardiomyopathy (NICM) with improved ejection fraction (impEF). Methods and results Consecutive NICM patients with baseline LVEF = 1 LVEF assessment after baseline were included. ImpEF was defined as a baseline LVEF = 10% point increase from baseline LVEF and LVEF >40%. Transient impEF was defined by the documentation of recurrent LVEF <= 40% during follow-up. The primary endpoint was a composite of all-cause death, heart transplantation and left ventricular assist device (D/HT/LVAD). Among 800 patients, 460 (57%) had impEF (median time to improvement 13 months). Transient impEF was observed in 189 patients (41% of the overall impEF group) and was associated with higher risk of D/HT/LVAD compared with persistent impEF at multivariable analysis (hazard ratio 2.54; 95% confidence interval 1.60-4.04). The association of declining LVEF with the risk of D/HT/LVAD was non-linear, with a steep increase up to 8% points reduction, then remaining stable. Conclusions In NICM, a 57% rate of impEF was observed. However, recurrent decline in LVEF was observed in approximate to 40% of impEF patients and it was associated with an increased risk of D/HT/LVAD

Natural History of Dilated Cardiomyopathy in Children

The long-term progression of idiopathic dilated cardiomyopathy (DCM) in pediatric patients compared with adult patients has not been previously characterized. In this study, we compared outcome and long-term progression of pediatric and adult DCM populations

Value of Strain Imaging and Maximal Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy

Longitudinal strain (LS) has been shown to be predictive of outcome in hypertrophic cardiomyopathy (HC). Percent predicted peak oxygen uptake (ppVO2), among other cardiopulmonary exercise testing (CPX) metrics, is a strong predictor of prognosis in HC. However, there has been limited investigation into the combination of LS and CPX metrics. This study sought to determine how LS and parameters of exercise performance contribute to prognosis in HC. One hundred and thirty-one consecutive patients with HC who underwent CPX and stress echocardiography were included. Global, septal, and lateral LS were assessed at rest and stress. Eighty matched individuals were used as controls. Patients were followed for the composite end point of death and worsening heart failure. All absolute LS components were lower in patients with HC than in controls (global 14.3\u2009\ub1\u20094.0% vs 18.8\u2009\ub1\u20092.2%, p 52\u2009ml/m2, and ppVO2 <80%. The combination of lateral LS, LAVI, and ppVO2 presents a simple model for outcome prediction

Left Ventricular Response to Cardiac Resynchronization Therapy: Insights From Hemodynamic Forces Computed by Speckle Tracking

Aims: Despite continuous efforts in improving the selection process, the rate of non-responders to cardiac resynchronization therapy (CRT) remains high. Recent studies on intraventricular blood flow suggested that the alignment of hemodynamic forces (HDFs) may be a reproducible biomarker of mechanical dyssynchrony. We aimed to explore the relationship between pacing-induced realignment of HDFs and positive response to CRT. Methods and results: We retrospectively analyzed 38 patients from the CRT database of our institution fulfilling the inclusion criteria for HDFs-related echocardiographic assessment early pre and post CRT implantation, with available mid-term follow-up ( 65 6 months) evaluation. Standard echocardiographic and deformation parameters early pre and post CRT implantation were integrated with the measurement of HFDs through novel methods based on speckle-tracking analysis. At midterm follow-up 71% of patients were classified as responders (reduction of Left Ventricular Systolic Volume Indexed 65 15%). Patients did not display significant changes between close evaluations pre and post-implant in terms of ejection fraction and strain metrics. A significant reduction of the ratio between the amplitudes of transversal and longitudinal force components was found. The variation of this ratio strongly correlates (R2 =0.60) with Left Ventricular (LV) end-systolic volume variation at mid-term follow up. Conclusion: Pacing-induced realignment of HDFs is associated with CRT efficacy at follow up. These preliminary results claim for dedicated prospective clinical studies testing the potential impact of HDFs study for patient selection and pacing optimization in CRT