Heart failure with mid-range or mildly reduced ejection fraction.
Savarese Gianluigi,Stolfo Davide,Sinagra Gianfranco,Lund Lars H
Nature reviews. Cardiology
Left ventricular ejection fraction (EF) remains the major parameter for diagnosis, phenotyping, prognosis and treatment decisions in heart failure. The 2016 ESC heart failure guidelines introduced a third EF category for an EF of 40-49%, defined as heart failure with mid-range EF (HFmrEF). This category has been largely unexplored compared with heart failure with reduced EF (HFrEF; defined as EF <40% in this Review) and heart failure with preserved EF (HFpEF; defined as EF ≥50%). The prevalence of HFmrEF within the overall population of patients with HF is 10-25%. HFmrEF seems to be an intermediate clinical entity between HFrEF and HFpEF in some respects, but more similar to HFrEF in others, in particular with regard to the high prevalence of ischaemic heart disease in these patients. HFmrEF is milder than HFrEF, and the risk of cardiovascular events is lower in patients with HFmrEF or HFpEF than in those with HFrEF. By contrast, the risk of non-cardiovascular adverse events is similar or greater in patients with HFmrEF or HFpEF than in those with HFrEF. Evidence from post hoc and subgroup analyses of randomized clinical trials and a trial of an SGLT1-SGLT2 inhibitor suggests that drugs that are effective in patients with HFrEF might also be effective in patients with HFmrEF. Although the EF is a continuous measure with considerable variability, in this comprehensive Review we suggest that HFmrEF is a useful categorization of patients with HF and shares the most important clinical features with HFrEF, which supports the renaming of HFmrEF to HF with mildly reduced EF.
Effects of cardiac resynchronization therapy on left ventricular remodeling and dyssynchrony in patients with left ventricular noncompaction and heart failure.
Qiu Qiong,Chen Yang-xin,Mai Jing-ting,Yuan Wo-liang,Wei Yu-lin,Liu Ying-mei,Yang Li,Wang Jing-Feng
The international journal of cardiovascular imaging
Left ventricular noncompaction (LVNC) is a rare cardiomyopathy with high incidence of heart failure (HF). It is unclear whether LVNC patients with desynchronized HF would benefit from cardiac resynchronization therapy (CRT). In order to evaluate the effect of CRT on LVNC, this study explored left ventricular (LV) remodeling and mechanical synchronicity before and after CRT in LVNC patients, and compare with that in idiopathic dilated cardiomyopathy (DCM) patients. We collected 15 LVNC and 30 matched DCM patients. All the patients underwent clinical evaluation,electrocardiogram and echocardiography before CRT and ≥6 months later. LV response was defined as ≥15 % decrease in LV end-systolic volume (LVESV). Longitudinal synchronicity was quantified by YU-index using tissue Doppler imaging. The time delay of peak radial strain from anteroseptal to posterior wall, which derived from speckle tracking imaging, was used to quantify radial synchronicity. In LVNC group, LV ejection fraction increased from 27.6 ± 5.5 to 39.1 ± 7.0 % (P < 0.01) during follow-up, but LV volumes did not change significantly (both P > 0.05). Five LVNC patients (33.3 %) responded to CRT, and all of them were super-responders (reduction in LVESV > 30 %). In addition, the number of noncompacted segments and the thickness ratio of noncompacted to compacted myocardium decreased (both P < 0.05). Inter-ventricular, longitudinal and radial intra-ventricular dyssynchrony also reduced significantly (all P < 0.05). Compared with DCM group, there was no significant difference in LV response rate (33.3 vs. 60.0 %, P = 0.092), improvement of LV function and dyssynchrony index (all P < 0.05). In conclusion, CRT improved heart function, morphology and mechanical dyssynchrony in LVNC patients.
Effect of Sex on Reverse Remodeling in Chronic Systolic Heart Failure.
Aimo Alberto,Vergaro Giuseppe,Castiglione Vincenzo,Barison Andrea,Pasanisi Emilio,Petersen Christina,Chubuchny Vladyslav,Giannoni Alberto,Poletti Roberta,Maffei Silvia,Januzzi James L,Passino Claudio,Emdin Michele
JACC. Heart failure
OBJECTIVES:This study sought to investigate sex-related differences in reverse remodeling (RR). BACKGROUND:RR, that is, the recovery from left ventricular (LV) dilation and dysfunction in response to treatment for heart failure (HF), is associated with improved prognosis. METHODS:Data from patients with stable systolic HF (LV ejection fraction [LVEF] of <50%) undergoing 2 transthoracic echocardiograms within 12 ± 2 months were analyzed. Reverse remodeling was defined as a ≥15% reduction in LV end-systolic volume index. RESULTS:A total of 927 patients were evaluated (68 ± 12 years; median LVEF = 35% [interquartile range: 30% to 43%]; 27% women). Ischemic HF was less often encountered in women (33% vs. 60%, respectively; p < 0.001), whereas most characteristics did not differ with regard to sex. Women showed a higher incidence of RR (41% vs. 27%, respectively; p < 0.001), despite similar baseline LV volume and function. RR was more frequent among women in the subgroups with either ischemic or nonischemic HF, as well as in all categories of systolic dysfunction (LVEF ≤35% or >35%, according to current indication for device implantation, and LVEF <40% or 40% to 50% according to the definition of HF with reduced or mid-range EF). In the whole population, female sex was an independent predictor of RR (hazard ratio: 1.54; 95% confidence interval: 1.11 to 2.14; p = 0.011), together with cause of HF, disease duration, and left bundle branch block. Female sex was again an independent predictor of RR in all LVEF categories. CONCLUSIONS:Reverse remodeling is more frequent among women, regardless of cause and severity of LV dysfunction. Female sex is an independent predictor of RR in all categories of LV systolic dysfunction.
Meta-Analysis of Atrial Fibrillation Ablation in Patients with Systolic Heart Failure.
Ruzieh Mohammed,Foy Andrew J,Aboujamous Nader M,Moroi Morgan K,Naccarelli Gerald V,Ghahramani Mehrdad,Kanjwal Shaffi,Marine Joseph E,Kanjwal Khalil
Atrial fibrillation (AF) and heart failure (HF) are two common conditions that often coexist and predispose each to one another. AF increases hospitalization rates and overall mortality in patients with HF. The current available therapeutic options for AF in patients with HF are diverse and guidelines do not provide a clear consensus regarding the best management approach. To determine if catheter ablation for AF is superior to medical therapy alone in patients with coexisting HF, we conducted this systematic review and meta-analysis. The primary outcomes evaluated are left ventricular ejection fraction (LVEF), Minnesota Living with Heart Failure Questionnaire (MLWHFQ) scores, 6-minute walk test (6MWT) distance, heart failure hospitalizations, and mortality. The results are presented as a mean difference for continuous outcome measures and odds ratios for dichotomous outcomes (using Mantel-Haenszel random effects model). 7 full texts met inclusion criteria, including 856 patients. AF catheter ablation was associated with a significant increase in LVEF (mean difference 6.8%; 95% CI: 3.5 - 10.1; P<0.001) and 6MWT (mean difference 29.3; 95% CI: 11.8 - 46.8; P = 0.001), and improvement in MLWHFQ (mean difference -12.1; 95% CI: -20.9 - -3.3; P = 0.007). The risk of all-cause mortality was significantly lower in the AF ablation arm (OR 0.49; 95% CI: 0.31 - 0.77; P = 0.002). In conclusion, atrial fibrillation ablation in patients with systolic heart failure is associated with significant improvement in LVEF, quality of life, 6MWT, and overall mortality.
Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.
Byrne Nikole J,Levasseur Jody,Sung Miranda M,Masson Grant,Boisvenue Jamie,Young Martin E,Dyck Jason R B
AIMS:Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes. METHODS AND RESULTS:Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery. CONCLUSIONS:The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery.
Hydrochlorothiazide modulates ischemic heart failure-induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats.
Luo Jinghong,Chen Xuanlan,Luo Chufan,Lu Guihua,Peng Longyun,Gao Xiuren,Zuo Zhiyi
AIMS:Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)-β/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects. METHODS:Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham-operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II. RESULTS:After eight-week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF-β and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II-induced TGF-β1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts. CONCLUSIONS:Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects.
Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients With Chronic Heart Failure and Iron Deficiency.
Charles-Edwards Geoffrey,Amaral Nelson,Sleigh Alison,Ayis Salma,Catibog Norman,McDonagh Theresa,Monaghan Mark,Amin-Youssef George,Kemp Graham J,Shah Ajay M,Okonko Darlington O
BACKGROUND:Iron repletion augments exercise capacity in chronic heart failure (HF), but there is a lack of mechanistic data explaining how iron could augment exercise performance despite minimal changes in hemoglobin (Hb). Besides Hb, iron is an obligate component of mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine (PCr). Dynamic phosphorus magnetic resonance spectroscopy is a noninvasive tool that quantifies in vivo muscle energetics by measuring the kinetics of PCr recovery after exertion. We tested the hypothesis that intravenous iron repletion in chronic HF enhances skeletal muscle energetics as reflected by shorter PCr recovery half-times (PCr t) on phosphorus magnetic resonance spectroscopy. METHODS:We enrolled 40 patients (50% anemic) with chronic HF, New York Heart Association class ≥II, left ventricular ejection fraction ≤45%, and iron deficiency (ferritin<100 μg/L or 100-300 μg/L with transferrin saturation <20%). Subjects underwent stratified (anemic versus nonanemic) randomization (1:1) to a single, double-blinded, total dose infusion of iron isomaltoside or saline placebo with end points reassessed early at 2 weeks posttreatment to minimize confounding from exercise adaptation. The primary end point was PCr t at 2 weeks. Secondary end points included ADP recovery half-time (ADP t energetic marker), iron status, symptoms, Hb, exercise capacity, and safety. RESULTS:In the total population, treatment groups were similar at baseline. At 2 weeks, iron isomaltoside improved PCr t (adjusted difference, -6.8 s; 95% CI, 11.5 to -2.1; P=0.006), ADP t (-5.3 s; 95% CI, -9.7 to -0.9; P=0.02), ferritin (304 ng/mL; 95% CI, 217-391; P<0.0001), transferrin saturation (6.8%; 95% CI, 2.7-10.8; P=0.002), New York Heart Association class (-0.23; 95% CI, -0.46 to -0.01; P=0.04), resting respiratory rate (-0.7 breaths/min; 95% CI, -1.2 to -0.2; P=0.009), and postexercise Borg dyspnea score (-2.0; 95% CI, -3.7 to -0.3; P=0.04), but not Hb (2.4 g/L; 95% CI, -3.5 to 8.4; P=0.41). Adverse events were similar between groups. In subgroup analyses, iron isomaltoside improved PCr t in anemic (-8.4 s; 95% CI, -16.7 to -0.2; P=0.04) and nonanemic (-5.2 s; 95% CI, -10.6 to 0.2; P=0.06) cohorts. CONCLUSIONS:In patients with chronic HF and iron deficiency, a total repletion dose of iron isomaltoside given at a single sitting is well tolerated and associated with faster skeletal muscle PCr t at 2 weeks, implying better mitochondrial function. Augmented skeletal muscle energetics might therefore be an important mechanism via which iron repletion confers benefits in chronic HF despite minimal Hb changes. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005592-13/GB . Unique identifier: EudraCT 2012-005592-13.
Progression of matrixin and cardiokine expression patterns in an ovine model of heart failure and recovery.
Quttainah Mohammed,Al-Hejailan Reem,Saleh Soad,Parhar Ranjit,Conca Walter,Bulwer Bernard,Moorjani Narain,Catarino Pedro,Elsayed Raafat,Shoukri Mohammed,AlJufan Mansour,AlShahid Maie,Ouban Abderrahman,Al-Halees Zohair,Westaby Stephen,Collison Kate,Al-Mohanna Futwan
International journal of cardiology
BACKGROUND:The molecular mechanisms underlying the geometrical changes of the left ventricle during the progression to heart failure and recovery are not well defined. OBJECTIVE:Here we investigate the involvement of matrixins and cardiokines in an ovine model of pressure-induced left ventricular failure (LVF). METHODS:Fifteen sheep underwent supracoronary aortic banding with an inflatable cuff. A controlled and progressive increase of LV pressure was monitored echocardiographically. Endomyocardial biopsies were collected throughout the development of LVF and subsequent recovery after pressure unloading. RESULTS:Thirteen sheep developed LVF with a subsequent recovery. Peak left ventricular hypertrophy (LVH) and dilatation (LVD) occurred at 31.5 ± 1.6 weeks and 102.7 ± 2.2 weeks post-banding respectively, with an increase in LV internal diameter in diastole (LVIDd 5.11 ± 0.12 compared to the control 3.37 ± 0.07 cm, p<0.001), with preserved LV ejection fraction (LVEF). Reduced LVEF became evident 116.5 ± 2.7 weeks post-banding. Clinical and echocardiographic improvements were observed following deflation of the aortic banding cuff. By 138.1 ± 3.1 weeks cardiac performance recovered with restoration of LVEF. Significant changes in the expression of matrix metalloproteinases (MMP)-1, -2, -3, vascular endothelial cell growth factor (VEGF), fibroblast growth factor (FGF)-2, interferon (INF)-α-2 and soluble CD40 ligand (sCD40L) were observed throughout the progression to failure and recovery. CONCLUSIONS:We used an ovine model to study reversible LV remodelling without interruption and found significant changes in matrixin and cardiokine expression during LV progression to failure and recovery.
Changes in collagen metabolism account for ventricular functional recovery following beta-blocker therapy in patients with chronic heart failure.
Fukui Miho,Goda Akiko,Komamura Kazuo,Nakabo Ayumi,Masaki Mitsuru,Yoshida Chikako,Hirotani Shinichi,Lee-Kawabata Masaaki,Tsujino Takeshi,Mano Toshiaki,Masuyama Tohru
Heart and vessels
While beta blockade improves left ventricular (LV) function in patients with chronic heart failure (CHF), the mechanisms are not well known. This study aimed to examine whether changes in myocardial collagen metabolism account for LV functional recovery following beta-blocker therapy in 62 CHF patients with reduced ejection fraction (EF). LV function was echocardiographically measured at baseline and 1, 6, and 12 months after bisoprolol therapy along with serum markers of collagen metabolism including C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase (MMP)-2. Deceleration time of mitral early velocity (DcT) increased even in the early phase, but LVEF gradually improved throughout the study period. Heart rate (HR) was reduced from the early stage, and CITP gradually decreased. LVEF and DcT increased more so in patients with the larger decreases in CITP (r = -0.33, p < 0.05; r = -0.28, p < 0.05, respectively), and HR (r = -0.31, p < 0.05; r = -0.38, p < 0.05, respectively). In addition, there were greater decreases in CITP, MMP-2 and HR from baseline to 1, 6, or 12 months in patients with above-average improvement in LVEF than in those with below-average improvement in LVEF. Similar results were obtained in terms of DcT. There was no significant correlation between the changes in HR and CITP. In conclusion, improvement in LV systolic/diastolic function was greatest in patients with the larger inhibition of collagen degradation. Changes in myocardial collagen metabolism are closely related to LV functional recovery somewhat independently from HR reduction.
Left ventricular ejection fraction as therapeutic target: is it the ideal marker?
Katsi V,Georgiopoulos G,Laina A,Koutli E,Parissis J,Tsioufis C,Nihoyannopoulos P,Tousoulis D
Heart failure reviews
Heart failure (HF) consists the fastest growing clinical cardiac disease. HF patients are categorized on the basis of underlying left ventricular ejection fraction (LVEF) into HF with preserved EF (HFpEF), reduced LVEF (HFrEF), and mid-range LVEF (HFmrEF). While LVEF is the most commonly used surrogate marker of left ventricular (LV) systolic function, the implementation of two-dimensional echocardiography in estimating this parameter imposes certain caveats on current HF classification. Most importantly, LVEF could fluctuate in repeated measurements or even recover after treatment, thus blunting the borders between proposed categories of HF and enabling upward classification of patients. Under this prism, we sought to summarize possible procedures to improve systolic function in patients with HFrEF either naturally or by the means of pharmacologic and non-pharmacologic treatment and devices. Therefore, we reviewed established pharmacotherapy, including beta-blockers, inhibitors of renin-angiotensin-aldosterone axis, statins, and digoxin as well as novel treatments like sacubitril-valsartan, ranolazine, and ivabradine. In addition, we assessed evidence in favor of cardiac resynchronization therapy and exercise training programs. Finally, innovative therapeutic strategies, including stem cells, xanthine oxidase inhibitors, antibiotic regimens, and omega-3 polyunsaturated fatty acids, were also taken into consideration. We concluded that LVEF is subject to changes in HF after intervention and besides the aforementioned HFrEF, HFpEF, and HFmrEF categories, a new entity of HF patients with recovered LVEF should be acknowledged. An improved global and refined LV function assessment by sophisticated imaging modalities and circulating biomarkers is expected to render HF classification more accurate and indicate patients with viable-yet dysfunctional-myocardium and favorable characteristics as the ideal candidates for LVEF recovery by individualized HF therapy.
Outcomes and predictors of recovery in acute-onset cardiomyopathy: A single-center experience of patients undergoing endomyocardial biopsy for new heart failure.
Gilotra Nisha A,Bennett Mosi K,Shpigel Adam,Ahmed Haitham M,Rao Shaline,Dunn Justin M,Harrington Colleen,Freitag Tasha B,Halushka Marc K,Russell Stuart D
American heart journal
BACKGROUND:About one-third of patients with unexplained acute-onset heart failure (HF) recover left ventricular (LV) function; however, characterization of these patients in the setting of contemporary HF therapies is limited. We aim to describe baseline characteristics and predictors of recovery in patients with acute-onset cardiomyopathy. METHODS:We previously described 851 patients with unexplained HF undergoing endomyocardial biopsy. In this study, 235 patients with acute-onset HF were further retrospectively examined. RESULTS:Follow-up LV ejection fraction (LVEF) was available for 138 patients. At 1 year, 48 of 138 (33%) had LVEF recovery (follow-up LVEF ≥50%), and 90 of 138 (65%) had incomplete or lack of recovery. Higher cardiac index (P=.019), smaller LV diastolic diameter (P=.002), and lack of an intraventricular conduction delay (IVCD) (P=.002) were associated with LVEF recovery. IVCD (P=.001) and myocarditis (P=.016) were independent predictors of the composite end point of death, LV assist device placement, and/or transplant at 1 year. Those with an IVCD had a significantly lower 1-year survival than those without (P=.007). CONCLUSIONS:Patients with a smaller LV end-diastolic diameter, higher cardiac index, and lack of IVCD at presentation for acute-onset HF were more likely to have LVEF recovery. IVCD was a poor prognostic marker in all patients presenting with acute cardiomyopathy.
Characteristics and outcomes of HFpEF with declining ejection fraction.
Park Jin Joo,Park Chan Soon,Mebazaa Alexandre,Oh Il-Young,Park Hyun-Ah,Cho Hyun-Jai,Lee Hae-Young,Kim Kye Hun,Yoo Byung-Su,Kang Seok-Min,Baek Sang Hong,Jeon Eun-Seok,Kim Jae-Joong,Cho Myeong-Chan,Chae Shung Chull,Oh Byung-Hee,Choi Dong-Ju
Clinical research in cardiology : official journal of the German Cardiac Society
OBJECTIVE:Some patients with heart failure with preserved ejection fraction (HFpEF) experience declining of left-ventricular ejection fraction (LVEF) during follow-up. We aim to investigate the characteristics and outcomes of patients with HF with declining ejection fraction (HFdEF). METHODS:We analyzed a prospective, nationwide multicenter cohort with consecutive patients with acute HF enrolled from March 2011 to December 2014. HFpEF was defined as LVEF ≥ 50% at index admission. After 1 year, HFpEF patients were further classified as HFdEF (LVEF ≥ 50% at admission and < 50% at 1 year), and persistent HFpEF (LVEF ≥ 50% both at admission and 1 year). Primary outcome was 4-year all-cause mortality according to HF type from HFdEF diagnosis. RESULTS:Of patients with HFpEF, 426 (90.4%) were diagnosed as having persistent HFpEF and 45 (9.6%) as having HFdEF. Natriuretic peptide level was an independent predictor of HFdEF (natriuretic peptide level > median: odds ratio: 3.20, 95% confidence interval [CI]: 1.42-7.25, P = 0.005). During 4-year follow-up, patients with HFdEF had higher mortality than those with persistent HFpEF (Log-rank P < 0.001). After adjustment, HFdEF was associated with an almost twofold increased risk for mortality (hazard ratio 1.82, 95% CI 1.13-2.96, P = 0.015). The use of beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists was not associated with improved prognosis of patients with HFdEF. CONCLUSIONS:HFdEF is a distinct HF type with grave outcomes. Further investigations that focus on HFdEF are warranted to better understand and develop treatment strategies for these high-risk patients. CLINICAL TRIAL REGISTRATION:ClinicalTrial.gov identifier: NCT01389843. URL: https://clinicaltrials.gov/ct2/show/NCT01389843.
Biomarkers to Predict Reverse Remodeling and Myocardial Recovery in Heart Failure.
Motiwala Shweta R,Gaggin Hanna K
Current heart failure reports
Left ventricular remodeling appears to be a critical link between cardiac injury and the development and progression of heart failure with reduced ejection fraction (HFrEF). Several drug and device therapies that modify and reverse the remodeling process in patients with HFrEF are closely associated with improvement in clinical outcomes. Reverse remodeling, including partial or complete recovery of systolic function and structure, is possible but its determinants are incompletely understood. Methods to predict reverse remodeling in response to therapy are not well defined. Though non-invasive imaging techniques remain the most widely used methods of assessing reverse remodeling, serum biomarkers are now being investigated as more specific, mechanistically driven, and clinically useful predictors of reverse remodeling. Biomarkers that reflect myocyte stretch and stress, myocyte injury and necrosis, inflammation and fibrosis, and extracellular matrix turnover may be particularly valuable for predicting pathophysiologic changes and prognosis in individual patients. Their use may ultimately allow improved application of precision medicine in chronic HF.
Is heart failure with midrange ejection fraction similar to preserved ejection fraction? Against.
Revista clinica espanola
The new European guidelines (2016) for heart failure (HF) include the concept of HF with intermediate left ventricular ejection fraction (LVEF), i.e. an LVEF between 40 and 49%. Although few studies have been carried out, there are claims that HF with intermediate LVEF is not the same as HF with preserved LVEF. Perhaps the most consistent claim is the high percentage of associated ischemic heart disease, which could reflect LVEF recovery after adequate anti-ischemic treatment of HF with depressed LVEF, or even the progressive deterioration of LVEF following an ischemic event.
Recovery from left ventricular dysfunction was associated with the early introduction of heart failure medical treatment in cancer patients with anthracycline-induced cardiotoxicity.
Ohtani Kisho,Fujino Takeo,Ide Tomomi,Funakoshi Kouta,Sakamoto Ichirou,Hiasa Ken-Ichi,Higo Taiki,Kamezaki Kenjiro,Akashi Koichi,Tsutsui Hiroyuki
Clinical research in cardiology : official journal of the German Cardiac Society
BACKGROUND:Left ventricular (LV) dysfunction due to anthracycline-induced cardiotoxicity (AIC) has been believed to be irreversible. However, this has not been confirmed and standard medical treatment for heart failure (HF) including renin-angiotensin inhibitors and β-blockers may lead to its recovery. METHODS AND RESULTS:We thus retrospectively studied 350 cancer patients receiving anthracycline-based chemotherapy from 2001 to 2015 in our institution. Fifty-two patients (14.9%) developed AIC with a decrease in LV ejection fraction (LVEF) of 24.1% at a median time of 6 months [interquartile range (IQR) 4-22 months] after anthracycline therapy. By multivariate analysis, AIC was independently associated with cardiac comorbidities including ischemic heart disease, valvular heart disease, arrhythmia, and cardiomyopathy [odds ratio (OR) 6.00; 95% confidence interval (CI) 2.27-15.84, P = 0.00044), lower baseline LVEF (OR per 1% 1.09; 95% CI 1.04-1.14, P = 0.00034). During the median follow-up of 3.2 years, LV systolic dysfunction recovered among 33 patients (67.3%) with a median time of 4 months (IQR 2-6 months), which was independently associated with the introduction of standard medical treatment for HF (OR 9.39; 95% CI 2.27-52.9, P = 0.0014) by multivariate analysis. CONCLUSION:Early initiation of standard medical treatment for HF may lead to LV functional recovery in AIC.
Parameters of repolarization heterogeneity are associated with myocardial recovery in acute heart failure.
Prenner Stuart B,Swat Stanley A,Ng Jason,Baldridge Abigail,Wilcox Jane E
International journal of cardiology
BACKGROUND:Heart failure (HF) with recovered ejection fraction (HFrecEF) is an increasingly recognized yet not well understood phenotype. Little is known about electrical parameters associated with myocardial recovery in acute systolic HF. METHODS:We identified a subset of 87 patients from a non-ischemic cardiomyopathy cohort with left ventricular ejection fraction (LVEF) < 40% during index HF hospitalization. HFrecEF was defined as follow-up LVEF ≥40% and ≥ 10% improvement from baseline. We analyzed baseline and follow up electrocardiograms (ECG) in this group for several electrical parameters known to reflect repolarization heterogeneity. RESULTS:Among 87 patients, 30 (34%) patients recovered in a median of 122 (IQR: 58-275) days after index hospitalization. Baseline demographics were similar among HFrecEF versus persistent HFrEF except for increased diabetes in the persistent HFrEF cohort. Patients with HFrecEF had baseline decreased QRST angle, decreased QT dispersion, and less negative signed JT area compared to persistent HFrEF. Patients with HFrecEF had greater decrease in QT dispersion and QTc duration, and greater increase in the signed JT and TpTe areas over time. Baseline QRST angle correlated with longitudinal and circumferential strain and myocardial systolic performance (MSP). Signed JT area correlated with increased baseline LVEF, smaller baseline LV dimensions, increased longitudinal and circumferential strain, and MSP. Signed TpTe correlated with increased longitudinal and circumferential strain, and MSP. CONCLUSIONS:Several conventional and novel ECG parameters that reflect repolarization heterogeneity may differentiate patients with acute HF who ultimately recover LVEF. These parameters are associated with baseline structural parameters and are dynamic during recovery.
Baseline Longitudinal Strain Predicts Recovery of Left Ventricular Ejection Fraction in Hospitalized Patients With Nonischemic Cardiomyopathy.
Swat Stanley A,Cohen David,Shah Sanjiv J,Lloyd-Jones Donald M,Baldridge Abigail S,Freed Benjamin H,Vorovich Esther E,Yancy Clyde W,Jonnalagadda Siddhartha R,Prenner Stuart,Kim Daniel,Wilcox Jane E
Journal of the American Heart Association
Background Heart failure ( HF ) with "recovered" ejection fraction ( HF rec EF ) is an emerging phenotype, but no tools exist to predict ejection fraction ( EF ) recovery in acute HF . We hypothesized that indices of baseline cardiac structure and function predict HF rec EF in nonischemic cardiomyopathy and reduced EF . Methods and Results We identified a nonischemic cardiomyopathy cohort with EF <40% during the first HF hospitalization (n=166). We performed speckle-tracking echocardiography to measure longitudinal, circumferential, and radial strain, and the average of these measures (myocardial systolic performance). HF rec EF was defined as follow-up EF ≥40% and ≥10% improvement from baseline EF . Fifty-nine patients (36%) achieved HF rec EF (baseline EF 26±7%; follow-up EF 51±7%) within a median of 135 (interquartile range 58-239) days after the first HF hospitalization. Baseline demographics, biomarker profiles, and comorbid conditions (except lower chronic kidney disease in HF rec EF ) were similar between HF rec EF and persistent reduced- EF groups. HF rec EF patients had smaller baseline left ventricular end-systolic dimension (3.6 versus 4.8 cm; P<0.01), higher baseline myocardial systolic performance (9.2% versus 8.1%; P=0.02), and improved survival (adjusted hazard ratio 0.27, 95% confidence interval 0.11, 0.62). We found a significant interaction between baseline left ventricular end-systolic dimension and absolute longitudinal strain. Among patients with left ventricular end-systolic dimension >4.35 cm, higher absolute longitudinal strain (≥8%) was associated with HF rec EF (unadjusted odds ratio=3.9, 95% CI )confidence interval 1.2, 12.8). Incorporation of baseline indices of cardiac mechanics with clinical variables resulted in a predictive model for HF rec EF with c-statistic=0.85. Conclusions Factors associated with achieving HF rec EF were specific to cardiac structure and indices of cardiac mechanics. Higher baseline absolute longitudinal strain is associated with HF rec EF among nonischemic cardiomyopathy patients with reduced EF and larger left ventricular dimensions.
Determinants of Left Ventricular Systolic Function Improvement Following Coronary Artery Revascularization in Heart Failure Patients With Reduced Ejection Fraction (HFrEF).
Adachi Yusuke,Sakakura Kenichi,Wada Hiroshi,Funayama Hiroshi,Umemoto Tomio,Fujita Hideo,Momomura Shin-Ichi
International heart journal
Revascularization therapy such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) should be considered for heart failure with reduced ejection fraction (HFrEF). However, revascularization therapy does not always improve left ventricular ejection fraction (LVEF). The purpose of this study was to investigate the determinants of LVEF improvement following revascularization in HFrEF patients. From 2,229 consecutive decompensated heart failure patients, a total of 47 HFrEF patients who underwent revascularization were included in the analysis. Improvement of LVEF was defined as [(LVEF during chronic phase) - (LVEF during acute phase)] ≥ 10%. Univariate and multivariate logistic regression analyses were applied to investigate the determinants of LVEF improvement. The prevalence of revascularization by PCIs including chronic total occlusion (CTO) was significantly greater in the improved EF group (45.0%) as compared to the non-improved EF group (11.1%) (P = 0.02). Multivariate logistic regression analysis revealed that revascularization by PCIs including CTO was the significant determinant of the LVEF improvement after adjusting for confounding factors (OR 5.43, 95% CI 1.06-27.74, P = 0.04). Optimal medical therapy (angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin II receptor blocker (ARB) and beta-blockers) was less frequently prescribed in patients with CABG (50.0% for ACE inhibitor and/or ARB and 41.7% for beta-blocker) than in patients without CABG (94.3% for both) (P < 0.01 and P < 0.001, respectively). In conclusion, revascularization by PCIs including CTO was the significant determinant of LVEF improvement in HFrEF patients. Our results underscore the importance of optimal medical therapy even if patients receive complete revascularization such as CABG.
Left ventricular ejection fraction recovery in patients with heart failure treated with intravenous iron: a pilot study.
Núñez Julio,Monmeneu José Vicente,Mollar Anna,Núñez Eduardo,Bodí Vicent,Miñana Gema,García-Blas Sergio,Santas Enrique,Agüero Jaume,Chorro Francisco J,Sanchis Juan,López-Lereu Maria Pilar
ESC heart failure
AIMS:In patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency, treatment with intravenous iron has shown a clinical improvement regardless of anaemic status. Cardiac magnetic resonance (CMR) T2* sequence has shown a potential utility for evaluating myocardial iron deficiency. We aimed to evaluate whether T2* sequence significantly changes after ferric carboximaltose (FCM) administration, and if such changes correlate with changes in left ventricle ejection fraction (LVEF). METHODS AND RESULTS:In this pilot study, we included eight patients with chronic symptomatic (New York Heart Association II-III) HFrEF and iron deficiency. A CMR, including T2* analysis, was performed before and at a median of 43 days (interquartile range = 35-48) after intravenous FCM administration. Pearson or Spearman correlation coefficient (r) was used for bivariate contrast as appropriate. A partial correlation analysis was performed between ΔLVEF and ΔT2* while controlling for anaemia status at baseline. Anaemia was present in half of patients. After FCM administration, T2* decreased from a median of 39.5 (35.9-48) to 32 ms (32-34.5), = 0.012. Simultaneously, a borderline increase in median of LVEF [40% (36-44.5) to 48.5% (38.5-53), = 0.091] was registered. In a bivariate correlational analysis, ΔT2* was highly correlated with ΔLVEF ( = -0.747, = 0.033). After controlling for anaemia at baseline, the association between ΔT2* and ΔLVEF persisted [(partial): -0.865, (partial): 0.748, = 0.012]. A median regression analysis backed-up these findings. CONCLUSIONS:In a small sample of patients with HFrEF and iron deficiency, myocardial iron repletion assessed by CMR was associated to left ventricular remodelling. Further studies are warranted.
Heart Failure with Myocardial Recovery - The Patient Whose Heart Failure Has Improved: What Next?
Nijst Petra,Martens Pieter,Mullens Wilfried
Progress in cardiovascular diseases
In an important number of heart failure (HF) patients substantial or complete myocardial recovery occurs. In the strictest sense, myocardial recovery is a return to both normal structure and function of the heart. HF patients with myocardial recovery or recovered ejection fraction (EF; HFrecEF) are a distinct population of HF patients with different underlying etiologies, demographics, comorbidities, response to therapies and outcomes compared to HF patients with persistent reduced (HFrEF) or preserved ejection fraction (HFpEF). Improvement of left ventricular EF has been systematically linked to improved quality of life, lower rehospitalization rates and mortality. However, mortality and morbidity in HFrecEF patients remain higher than in the normal population. Also, persistent abnormalities in biomarker and gene expression profiles in these patients lends weight to the hypothesis that pathological processes are ongoing. Currently, there remains a lack of data to guide the management of HFrecEF patients. This review will discuss specific characteristics, pathophysiology, clinical implications and future needs for HFrecEF.
Abnormal Global Longitudinal Strain Predicts Future Deterioration of Left Ventricular Function in Heart Failure Patients With a Recovered Left Ventricular Ejection Fraction.
Adamo Luigi,Perry Andrew,Novak Eric,Makan Majesh,Lindman Brian R,Mann Douglas L
Circulation. Heart failure
BACKGROUND:Patients with recovery of left ventricular ejection fraction (LVEF) remain at risk for future deterioration of LVEF. However, there are no tools to risk stratify these patients. We hypothesized that global longitudinal strain (GLS) could predict sustained recovery within this population. METHODS AND RESULTS:We retrospectively identified 96 patients with a reduced LVEF <50% (screening echocardiogram), whose LVEF had increased by at least 10% and normalized (>50%) on evidence-based medical therapies (baseline echocardiogram). We examined absolute GLS on the baseline echocardiogram in relation to changes in LVEF on a follow-up echocardiogram. Patients with recovered LVEF had a wide range of GLS. The GLS on the baseline study correlated with the LVEF at the time of follow-up (=0.33; <0.001). The likelihood of having an LVEF >50% on follow-up increased by 24% for each point increase in absolute GLS on the baseline study (odds ratio, 1.24; =0.001). An abnormal GLS (≤16%) at baseline had a sensitivity of 88%, a specificity of 46%, and an accuracy of 0.67 (<0.001) as a predictor of a decrease in LVEF >5% during follow-up. A normal GLS (>16%) on the baseline study had a sensitivity of 47%, a specificity of 83%, and an accuracy of 0.65 (=0.002) for predicting a stable LVEF (-5% to 5%) on follow-up. CONCLUSIONS:In patients with a recovered LVEF, an abnormal GLS predicts the likelihood of having a decreased LVEF during follow-up, whereas a normal GLS predicts the likelihood of stable LVEF during recovery.
Characteristics and Outcomes of Adult Outpatients With Heart Failure and Improved or Recovered Ejection Fraction.
Kalogeropoulos Andreas P,Fonarow Gregg C,Georgiopoulou Vasiliki,Burkman Gregory,Siwamogsatham Sarawut,Patel Akash,Li Song,Papadimitriou Lampros,Butler Javed
IMPORTANCE:Heart failure (HF) guidelines recognize that a subset of patients with HF and preserved left ventricular ejection fraction (LVEF) previously had reduced LVEF but experienced improvement or recovery in LVEF. However, data on these patients are limited. OBJECTIVE:To investigate the characteristics and outcomes of adult outpatients with HF and improved or recovered ejection fraction (HFrecEF). DESIGN, SETTING, AND PARTICIPANTS:Retrospective cohort study (inception period, January 1, 2012, to April 30, 2012) with 3-year follow-up at cardiology clinics (including HF subspecialty) in an academic institution. The dates of the analysis were May 21, 2015, to August 10, 2015. Participants were all outpatients 18 years or older who received care for a verified diagnosis of HF not attributed to specific cardiomyopathies or other special causes during the inception period. EXPOSURES:Type of HF at baseline, classified as HF with reduced ejection fraction (HFrEF) (defined as current LVEF ≤40%), HF with preserved ejection fraction (HFpEF) (defined as current and all previous LVEF reports >40%), and HF with recovered ejection fraction (HFrecEF) (defined as current LVEF >40% but any previously documented LVEF ≤40%). MAIN OUTCOMES AND MEASURES:Mortality, hospitalization rates, and composite end points. RESULTS:The study cohort comprised 2166 participants. Their median age was 65 years, 41.4% (896 of 2166) were female, 48.7% (1055 of 2166) were white and 45.2% (1368 of 2166) black, and 63.2% (1368 of 2166) had coronary artery disease. Preserved (>40%) LVEF at inception was present in 816 of 2166 (37.7%) patients. Of these patients, 350 of 2166 (16.2%) had previously reduced (≤40%) LVEF and were classified as having HFrecEF, whereas 466 of 2166 (21.5%) had no previous reduced LVEF and were classified as having HFpEF. The remaining 1350 (62.3%) patients were classified as having HFrEF. After 3 years, age and sex-adjusted mortality was 16.3% in patients with HFrEF, 13.2% in patients with HFpEF, and 4.8% in patients with HFrecEF (P < .001 vs HFrEF or HFpEF). Compared with patients with HFpEF and patients with HFrEF, patients with HFrecEF had fewer all-cause (adjusted rate ratio [RR] vs HFpEF, 0.71; 95% CI, 0.55-0.91; P = .007), cardiovascular (RR, 0.50; 95% CI, 0.35-0.71; P < .001), and HF-related (RR, 0.48; 95% CI, 0.30-0.76; P = .002) hospitalizations and were less likely to experience composite end points commonly used in clinical trials (death or cardiovascular hospitalization and death or HF hospitalization). CONCLUSIONS AND RELEVANCE:Outpatients with HFrecEF have a different clinical course than patients with HFpEF and HFrEF, with lower mortality, less frequent hospitalizations, and fewer composite end points. These patients may need to be investigated separately in outcomes studies and clinical trials.
Systolic function recovery in Heart Failure: Frequency, prognostic impact and predictors.
Pereira Joana,Chaves Vanessa,Tavares Sofia,Albuquerque Inês,Gomes Clara,Guiomar Verónica,Monteiro Ana,Ferreira Inês,Lourenço Patrícia,Bettencourt Paulo
International journal of cardiology
BACKGROUND:Systolic function recovery in patients with Heart failure (HF) with reduced ejection fraction (EF) is well recognized but not completely understood. We aimed to characterize HF patients with systolic function recovery, its prognostic impact and predictors. METHODS:We analysed patients followed in a HF clinic (2006-2015) with 2 echocardiograms performed. Partial recovery: EF recovery without attaining EF ≥ 50%; total recovery: patients reached EF ≥ 50%. Median follow-up from first echocardiogram: 69 months. Multivariate logistic regression models to determine recovery predictors. RESULTS:We analysed 304 patients with at least mild left ventricular dysfunction. During a median 34 months between echocardiogram re-evaluation 150 (49.3%) patients showed no EF recovery; 55 (18.1%) had partial recovery and 99 (32.6%) totally recovered. Mean patients age: 66; 71.1% men, high comorbidity burden; ischemic HF: 35.5%. Non-recovered patients were mostly men (80.7% vs 61.8% in partially; 61.6% in fully-recovered) with ischemic HF (46.0% vs 32.5% in partially; 21.2% in fully-recovered). Comorbidity burden, NYHA class and therapy were similar. During follow-up, 156 patients (46.7%) died. Patients with total recovery had a multivariate-adjusted 54% lower risk of dying when compared to non-recovered. Partially-recovered patients showed a non-significant adjusted 8% mortality reduction. Independent predictors of systolic function recovery were female gender(OR: 2.17, 95% CI 1.11-4.35), non-ischemic aetiology (OR: 2.78, 95% CI 1.35-5.56), and end diastolic left ventricular diameter < 60 mm (OR: 3.12, 95% CI 1.56-6.25). CONCLUSIONS:HF-recovered patients were mainly women with non-ischemic HF and smaller left ventricles. These patients had significantly better prognosis than those with persistently reduced EF.
The β-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection Fraction.
Reddy Yogesh N V,Obokata Masaru,Koepp Katlyn E,Egbe Alexander C,Wiley Brandon,Borlaug Barry A
RATIONALE:Pulmonary vascular resistance fails to decrease appropriately during exercise in patients with heart failure with preserved ejection fraction (HFpEF). Interventions that enhance pulmonary vasodilation might be beneficial in this cohort but could also worsen left atrial hypertension, exacerbating lung congestion. Intravenous β-agonists reduce pulmonary vascular resistance but are not suitable for chronic use. OBJECTIVE:We hypothesized that the inhaled β-adrenergic agonist albuterol would improve pulmonary vasodilation during exercise in patients with HFpEF, without increasing left heart filling pressures. METHODS AND RESULTS:We performed a randomized, double-blind, placebo-controlled trial testing the effects of inhaled albuterol on resting and exercise hemodynamics in subjects with HFpEF using high-fidelity micromanometer catheters and expired gas analysis. The primary end point was pulmonary vascular resistance during exercise. Subjects with HFpEF (n=30) underwent resting and exercise hemodynamic assessment and were then randomized 1:1 to inhaled, nebulized albuterol or placebo. Rest and exercise hemodynamic testing was then repeated. Albuterol improved the primary end point of exercise pulmonary vascular resistance as compared with placebo (-0.6±0.5 versus +0.1±0.7 WU; P=0.003). Albuterol enhanced cardiac output reserve and right ventricular pulmonary artery coupling, reduced right atrial and pulmonary artery pressures, improved pulmonary artery compliance, and enhanced left ventricular transmural distending pressure (all P <0.01), with no increase in pulmonary capillary hydrostatic pressures. CONCLUSIONS:Albuterol improves pulmonary vascular reserve in patients with HFpEF without worsening left heart congestion. Further study is warranted to evaluate the chronic efficacy of β-agonists in HFpEF and other forms of pulmonary hypertension. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov . Unique identifier: NCT02885636.
Heart failure with recovered ejection fraction.
Tanabe Kazuaki,Sakamoto Takahiro
Journal of echocardiography
Substantial or complete myocardial recovery occurs in many patients with heart failure (HF). HF patients with myocardial recovery or recovered left ventricular (LV) ejection fraction (EF; HFrecEF) are a distinct population of HF patients with different underlying etiologies, comorbidities, response to therapies, and outcomes compared with HF patients with persistent reduced or preserved EF. Improvement in LVEF has been systematically linked to improved quality of life, and lower rehospitalization rates and mortality. However, the mortality and morbidity in HFrecEF patients remain higher than those in the normal population. Currently, data to guide the management of HFrecEF patients are lacking. This review discusses specific characteristics, pathophysiology, and clinical implications for HFrecEF.
Benefits of chronic total coronary occlusion percutaneous intervention in patients with heart failure and reduced ejection fraction: insights from a cardiovascular magnetic resonance study.
Cardona Montserrat,Martín Victoria,Prat-Gonzalez Susanna,Ortiz José Tomás,Perea Rosario Jesús,de Caralt Teresa Maria,Masotti Mónica,Pérez-Villa Félix,Sabaté Manel
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
BACKGROUND:Chronic total occlusion percutaneous coronary intervention (CTO-PCI) can improve angina and left ventricular ejection fraction (LVEF). These benefits were not assessed in populations with heart failure with reduced ejection fraction (HFrEF). We studied the effect of CTO-PCI on left ventricular function and clinical parameters in patients with HFrEF. METHODS:Using cardiovascular magnetic resonance (CMR), we studied 29 patients with HFrEF and evidence of viability and/or ischemia in the territory supplied by a CTO who were successfully treated with CTO-PCI. In patients with multi-vessel disease, non-CTO PCI was also performed. Imaging parameters, clinical status, and brain natriuretic peptide (BNP) levels were evaluated before and 6 months after CTO-PCI. RESULTS:A decrease in left ventricular end-systolic volume (160 ± 54 ml vs. 143 ± 58 ml; p = 0.029) and an increase in LVEF (31.3 ± 7.4 % vs. 37.7 ± 8 %; p < 0.001) were observed. There were no differences in LVEF improvement between patients who underwent non-CTO PCI (n = 11) and those without this intervention (n = 18); (p = 0.73). The number of segments showing perfusion defects was significantly reduced (0.5 ± 1 vs. 0.2 ± 0.5; p = 0.043). Angina (p = 0.002) and NYHA functional class (p = 0.004) improved, and BNP levels decreased (p = 0.004) after CTO-PCI. CONCLUSIONS:In this group of patients with HFrEF showing CMR evidence of viability and/or ischemia within the territory supplied by the CTO, an improvement in ejection fraction, left ventricular end-systolic volume and ischemia burden was observed after CTO-PCI. Clinical and laboratory parameters also improved. TRIAL REGISTRATION:ClinicalTrials.gov NCT02570087 . Registered 6 October 2015.
Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2).
Van Tassell Benjamin W,Buckley Leo F,Carbone Salvatore,Trankle Cory R,Canada Justin M,Dixon Dave L,Abouzaki Nayef,Oddi-Erdle Claudia,Biondi-Zoccai Giuseppe,Arena Ross,Abbate Antonio
Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of confirmed HF cases in the United States. However, there are no highly effective evidence-based treatments currently available for these patients. Inflammation correlates positively with adverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, has been implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clinical trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 randomized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1 blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespiratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation in patients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co-primary endpoints will be placebo-corrected interval changes in peak oxygen consumption and ventilatory efficiency at week 12. In addition, secondary and exploratory analyses will investigate the effects of IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function, quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinical trial will add to the growing body of evidence on the role of inflammation in cardiovascular disease, specifically focusing on patients with HFpEF.
"Targeting the Heart" in Heart Failure: Myocardial Recovery in Heart Failure With Reduced Ejection Fraction.
Wilcox Jane E,Fonarow Gregg C,Ardehali Hossein,Bonow Robert O,Butler Javed,Sauer Andrew J,Epstein Stephen E,Khan Sadiya S,Kim Raymond J,Sabbah Hani N,Díez Javier,Gheorghiade Mihai
JACC. Heart failure
Myocardial recovery in heart failure (HF) is possible, but its determinants are not fully defined. At least partial functional improvement is possible with current evidence-based therapies. However, once significant HF symptoms develop, patients have varied trajectories, including: 1) structural and functional recovery; 2) stabilization (remission); and 3) acceleration to end-stage HF/death. All 3 trajectories may be interrupted by sudden death. These trajectories may represent the interplay of heterogeneous causality, genetic predeterminants, and disease phenotypes. Enhanced phenotypic description with cardiac magnetic resonance imaging, molecular imaging, or circulating biomarkers of the heterogeneous HF population may provide insights regarding specific biological targets amenable to existing and novel therapeutic strategies. The identification of patients in "remission," before progression to the end stage of predominantly nonviable tissue (e.g., fibrosis), has implications for clinical practice and future trials because such patients may be more likely to experience myocardial recovery (cardiac reserve). The identification of dysfunctional but viable myocardium and its diverse pathophysiological causes may provide opportunities to investigate existing and novel therapeutics aimed at enhancing myocardial recovery.
Catheter ablation for atrial fibrillation in heart failure with reduced ejection fraction: a systematic review and meta-analysis of randomized controlled trials.
AlTurki Ahmed,Proietti Riccardo,Dawas Ahmed,Alturki Hasan,Huynh Thao,Essebag Vidal
BMC cardiovascular disorders
BACKGROUND:Previous randomized controlled trials (RCT)s showed similar outcomes in patients with atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) treated with anti-arrhythmic drugs (AAD) compared to rate control therapy. We sought to evaluate whether catheter ablation is superior to medical therapy in patients with AF and HFrEF. METHODS:We searched electronic databases for all RCTs that compared catheter ablation and medical therapy (with or without use of AAD). We used random-effects models to summarize the studies. The primary end-point was all-cause mortality. Secondary outcomes included heart failure-related hospitalizations and change in left ventricular ejection fraction (LVEF). RESULTS:We retrieved and summarized 7 randomized controlled trials, enrolling 856 patients (429 in the catheter ablation arm and 427 in the medical therapy arm). Compared with medical therapy (including use of AAD), AF catheter ablation was associated with a significant reduction in mortality (risk ratio 0.50; 95% confidence interval [CI]: 0.34 to 0.74; P = 0.0005) and heart failure-related hospitalizations (risk ratio 0.56; 95% CI: 0.44 to 0.71; P < 0.0001). Furthermore, catheter ablation led to significant improvements in LVEF (weighted mean difference, 7.48; 95% CI: 3.71 to 11.26; P < 0.0001). CONCLUSIONS:Compared to medical therapy, including use of AAD, catheter ablation for AF was associated with a significant reduction in mortality and heart failure-related hospitalizations as well as an improvement in LVEF in patients with HFrEF. Larger trials are needed to confirm whether rhythm control with ablation is superior to rate control in patients with AF and heart failure.
The effects and costs of home-based rehabilitation for heart failure with reduced ejection fraction: The REACH-HF multicentre randomized controlled trial.
Dalal Hasnain M,Taylor Rod S,Jolly Kate,Davis Russell C,Doherty Patrick,Miles Jackie,van Lingen Robin,Warren Fiona C,Green Colin,Wingham Jennifer,Greaves Colin,Sadler Susannah,Hillsdon Melvyn,Abraham Charles,Britten Nicky,Frost Julia,Singh Sally,Hayward Christopher,Eyre Victoria,Paul Kevin,Lang Chim C,Smith Karen
European journal of preventive cardiology
BACKGROUND:Cardiac rehabilitation improves health-related quality of life (HRQoL) and reduces hospitalizations in patients with heart failure, but international uptake of cardiac rehabilitation for heart failure remains low. DESIGN AND METHODS:The aim of this multicentre randomized trial was to compare the REACH-HF (Rehabilitation EnAblement in CHronicHeart Failure) intervention, a facilitated self-care and home-based cardiac rehabilitation programme to usual care for adults with heart failure with reduced ejection fraction (HFrEF). The study primary hypothesis was that the addition of the REACH-HF intervention to usual care would improve disease-specific HRQoL (Minnesota Living with Heart Failure questionnaire (MLHFQ)) at 12 months compared with usual care alone. RESULTS:The study recruited 216 participants, predominantly men (78%), with an average age of 70 years and mean left ventricular ejection fraction of 34%. Overall, 185 (86%) participants provided data for the primary outcome. At 12 months, there was a significant and clinically meaningful between-group difference in the MLHFQ score of -5.7 points (95% confidence interval -10.6 to -0.7) in favour of the REACH-HF intervention group ( p = 0.025). With the exception of patient self-care ( p < 0.001) there was no significant difference in other secondary outcomes, including clinical events ( p > 0.05) at follow-up compared with usual care. The mean cost of the REACH-HF intervention was £418 per participant. CONCLUSIONS:The novel REACH-HF home-based facilitated intervention for HFrEF was clinically superior in disease-specific HRQoL at 12 months and offers an affordable alternative to traditional centre-based programmes to address current low cardiac rehabilitation uptake rates for heart failure.
Heart failure with preserved ejection fraction: New approaches to diagnosis and management.
Upadhya Bharathi,Kitzman Dalane W
The majority of older patients who develop heart failure (HF), particularly older women, have a preserved left ventricular ejection fraction (HFpEF). Patients with HFpEF have severe symptoms of exercise intolerance, poor quality-of-life, frequent hospitalizations, and increased mortality. The prevalence of HFpEF is increasing and its prognosis is worsening. However, despite its importance, our understanding of the pathophysiology of HFpEF is incomplete, and drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Originally viewed as a disorder due solely to abnormalities in left ventricular (LV) diastolic function, our understanding has evolved such that HFpEF is now understood as a systemic syndrome, involving multiple organ systems, likely triggered by inflammation and with an important contribution of aging, lifestyle factors, genetic predisposition, and multiple-comorbidities, features that are typical of a geriatric syndrome. HFpEF is usually progressive due to complex mechanisms of systemic and cardiac adaptation that vary over time, particularly with aging. In this review, we examine evolving data regarding HFpEF that may help explain past challenges and provide future directions to care patients with this highly prevalent, heterogeneous clinical syndrome.
Transition of Left Ventricular Ejection Fraction in Heart Failure.
Sakata Yasuhiko,Tsuji Kanako,Nochioka Kotaro,Shimokawa Hiroaki
Advances in experimental medicine and biology
Along with a worldwide epidemiological transition and dramatic increase in the elderly population, both the incidence and prevalence of heart failure (HF) are increasing worldwide. This epidemic of HF is characterized by an increase of HF with preserved left ventricular ejection fraction (LVEF) (HFpEF) and a decrease of HF with reduced LVEF (HFrEF). Of note, transition between HFpEF and HFrEF has been recently highlighted, since it significantly relates with prognosis. Our recent studies indicated that temporary changes in LVEF are common and associated with prognosis in patients with HF. In this chapter, we summarize recent findings on temporal changes in LVEF and their prognostic impact in HF patients, acknowledging that further studies are needed to fully elucidate the pathophysiology of LVEF recovery and deterioration to improve clinical outcomes of HF patients, and also to develop therapies targeting novel pathways of myocardial recovery.
Heart failure with preserved ejection fraction: current management and future strategies : Expert opinion on the behalf of the Nucleus of the "Heart Failure Working Group" of the German Society of Cardiology (DKG).
Tschöpe Carsten,Birner Christoph,Böhm Michael,Bruder Oliver,Frantz Stefan,Luchner Andreas,Maier Lars,Störk Stefan,Kherad Behrouz,Laufs Ulrich
Clinical research in cardiology : official journal of the German Cardiac Society
About 50% of all patients suffering from heart failure (HF) exhibit a reduced ejection fraction (EF ≤ 40%), termed HFrEF. The others may be classified into HF with midrange EF (HFmrEF 40-50%) or preserved ejection fraction (HFpEF, EF ≥ 50%). Presentation and pathophysiology of HFpEF is heterogeneous and its management remains a challenge since evidence of therapeutic benefits on outcome is scarce. Up to now, there are no therapies improving survival in patients with HFpEF. Thus, the treatment targets symptom relief, quality of life and reduction of cardiac decompensations by controlling fluid retention and managing risk factors and comorbidities. As such, renin-angiotensin-aldosterone inhibitors, diuretics, calcium channel blockers (CBB) and beta-blockers, diet and exercise recommendations are still important in HFpEF, although these interventions are not proven to reduce mortality in large randomized controlled trials. Recently, numerous new treatment targets have been identified, which are further investigated in studies using, e.g. soluble guanylate cyclase stimulators, inorganic nitrates, the angiotensin receptor neprilysin inhibitor LCZ 696, and SGLT2 inhibitors. In addition, several devices such as the CardioMEMS, interatrial septal devices (IASD), cardiac contractility modulation (CCM), renal denervation, and baroreflex activation therapy (BAT) were investigated in different forms of HFpEF populations and some of them have the potency to offer new hopes for patients suffering from HFpEF. On the basic research field side, lot of new disease-modifying strategies are under development including anti-inflammatory drugs, mitochondrial-targeted antioxidants, new anti-fibrotic and microRNA-guided interventions are under investigation and showed already promising results. This review addresses available data of current best clinical practice and management approaches based on expert experiences and summarizes novel approaches towards HFpEF.
Revisiting the physiological effects of exercise training on autonomic regulation and chemoreflex control in heart failure: does ejection fraction matter?
Andrade David C,Arce-Alvarez Alexis,Toledo Camilo,Díaz Hugo S,Lucero Claudia,Quintanilla Rodrigo A,Schultz Harold D,Marcus Noah J,Amann Markus,Del Rio Rodrigo
American journal of physiology. Heart and circulatory physiology
Heart failure (HF) is a global public health problem that, independent of its etiology [reduced (HFrEF) or preserved ejection fraction (HFpEF)], is characterized by functional impairments of cardiac function, chemoreflex hypersensitivity, baroreflex sensitivity (BRS) impairment, and abnormal autonomic regulation, all of which contribute to increased morbidity and mortality. Exercise training (ExT) has been identified as a nonpharmacological therapy capable of restoring normal autonomic function and improving survival in patients with HFrEF. Improvements in autonomic function after ExT are correlated with restoration of normal peripheral chemoreflex sensitivity and BRS in HFrEF. To date, few studies have addressed the effects of ExT on chemoreflex control, BRS, and cardiac autonomic control in HFpEF; however, there are some studies that have suggested that ExT has a beneficial effect on cardiac autonomic control. The beneficial effects of ExT on cardiac function and autonomic control in HF may have important implications for functional capacity in addition to their obvious importance to survival. Recent studies have suggested that the peripheral chemoreflex may also play an important role in attenuating exercise intolerance in HFrEF patients. The role of the central/peripheral chemoreflex, if any, in mediating exercise intolerance in HFpEF has not been investigated. The present review focuses on recent studies that address primary pathophysiological mechanisms of HF (HFrEF and HFpEF) and the potential avenues by which ExT exerts its beneficial effects.
Heart Failure With Preserved Ejection Fraction In Perspective.
Pfeffer Marc A,Shah Amil M,Borlaug Barry A
Approximately half of the patients with signs and symptoms of heart failure have a left ventricular ejection fraction that is not markedly abnormal. Despite the historically initial surprise, heightened risks for heart failure specific major adverse events occur across the broad range of ejection fraction, including normal. The recognition of the magnitude of the problem of heart failure with preserved ejection fraction in the past 20 years has spurred an explosion of clinical investigation and growing intensity of informative outcome trials. This article addresses the historic development of this component of the heart failure syndrome, including the epidemiology, pathophysiology, and existing and planned therapeutic studies. Looking forward, more specific phenotyping and even genotyping of subpopulations should lead to improvements in outcomes from future trials.
Frequency, predictors, and prognosis of ejection fraction improvement in heart failure: an echocardiogram-based registry study.
Ghimire Anukul,Fine Nowell,Ezekowitz Justin A,Howlett Jonathan,Youngson Erik,McAlister Finlay A
European heart journal
AIMS:To identify variables predicting ejection fraction (EF) recovery and characterize prognosis of heart failure (HF) patients with EF recovery (HFrecEF). METHODS AND RESULTS:Retrospective study of adults referred for ≥2 echocardiograms separated by ≥6 months between 2008 and 2016 at the two largest echocardiography centres in Alberta who also had physician-assigned diagnosis of HF. Of 10 641 patients, 3124 had heart failure reduced ejection fraction (HFrEF) (EF ≤ 40%) at baseline: while mean EF declined from 30.2% on initial echocardiogram to 28.6% on the second echocardiogram in those patients with persistent HFrEF (defined by <10% improvement in EF), it improved from 26.1% to 46.4% in the 1174 patients (37.6%) with HFrecEF (defined by EF absolute improvement ≥10%). On multivariate analysis, female sex [adjusted odds ratio (aOR) 1.66, 95% confidence interval (CI) 1.40-1.96], younger age (aOR per decade 1.16, 95% CI 1.09-1.23), atrial fibrillation (aOR 2.00, 95% CI 1.68-2.38), cancer (aOR 1.52, 95% CI 1.03-2.26), hypertension (aOR 1.38, 95% CI 1.18-1.62), lower baseline ejection fraction (aOR per 1% decrease 1.07 (1.06-1.08), and using hydralazine (aOR 1.69, 95% CI 1.19-2.40) were associated with EF improvements ≥10%. HFrecEF patients demonstrated lower rates per 1000 patient years of mortality (106 vs. 164, adjusted hazard ratio, aHR 0.70 [0.62-0.79]), all-cause hospitalizations (300 vs. 428, aHR 0.87 [0.79-0.95]), all-cause emergency room (ER) visits (569 vs. 799, aHR 0.88 [0.81-0.95]), and cardiac transplantation or left ventricular assist device implantation (2 vs. 10, aHR 0.21 [0.10-0.45]) compared to patients with persistent HFrEF. Females with HFrEF exhibited lower mortality risk (aHR 0.94 [0.88-0.99]) than males after adjusting for age, time between echocardiograms, clinical comorbidities, medications, and whether their EF improved or not during follow-up. CONCLUSION:HFrecEF patients tended to be younger, female, and were more likely to have hypertension, atrial fibrillation, or cancer. HFrecEF patients have a substantially better prognosis compared to those with persistent HFrEF, even after multivariable adjustment, and female patients exhibit lower mortality risk than men within each subgroup (HFrecEF and persistent HFrEF) even after multivariable adjustment.
Characteristics and prognosis of heart failure with improved compared with persistently reduced ejection fraction: A systematic review and meta-analyses.
Jørgensen Mads E,Andersson Charlotte,Vasan Ramachandran S,Køber Lars,Abdulla Jawdat
European journal of preventive cardiology
Aims We assessed the clinical characteristics and prognosis of chronic heart failure patients with improved ejection fraction (HFIEF) compared with persistently reduced ejection fraction (HFpREF) after evidence-based therapy. Methods and results We performed a meta-analysis including 24 eligible observational studies comparing 2663 HFIEF (≥5% left ventricular ejection fraction (LVEF) improvement) versus 8355 HFpREF patients who received recommended drug therapy, cardiac resynchronization therapy and/or intracardiac defibrillator. LVEF was assessed at baseline and reassessed after 19 ± 19 months. The primary endpoints were all-cause mortality and appropriate shocks. The mean duration of follow-up was 39 ± 12 months. Among HFIEF patients, LVEF improved 16.3 percentage points (95% confidence interval 15.9-16.6, p < 0.0001). Compared with HFpREF patients, HFIEF patients had a comparable mean age (60.9 years vs. 62.4 years, p = 0.11), were more often women (33% vs. 25%), had a higher prevalence of non-ischaemic heart failure (58% vs. 53%), less diabetes (27% vs. 28%), higher systolic blood pressure (127.5 ± 9 vs. 122 ± 12 mmHg) and lower left ventricle end-diastolic diameter (64.1 ± 3.7 vs. 67.4 ± 4.9 mmHg), all p-values < 0.05. Absolute risk of all-cause mortality was lower in HFIEF (5.8%) compared with HFpREF (17.5%) with a risk ratio of 0.34 (95% confidence interval 0.28-0.41), p < 0.001. Risk of appropriate shocks was significantly lower in HFIEF versus HFpREF (risk ratio 0.58 (95% confidence interval 0.46-0.74), p < 0.001). Conclusion In heart failure patients, we identified several baseline characteristics in favour of an improved LVEF, in response to evidence based therapy. Patients with improved LVEF had significantly lower risks of mortality and appropriate shocks compared with patients with persistently reduced LVEF.
Heart failure with preserved ejection fraction: controversies, challenges and future directions.
Zakeri Rosita,Cowie Martin R
Heart (British Cardiac Society)
Heart failure with preserved ejection fraction (HFpEF) comprises almost half of the population burden of HF. Because HFpEF likely includes a range of cardiac and non-cardiac abnormalities, typically in elderly patients, obtaining an accurate diagnosis may be challenging, not least due to the existence of multiple HFpEF mimics and a newly identified subset of patients with HFpEF and normal plasma natriuretic peptide concentrations. The lack of effective treatment for these patients represents a major unmet clinical need. Heterogeneity within the patient population has triggered debate over the aetiology and pathophysiology of HFpEF, and the neutrality of randomised clinical trials suggests that we do not fully understand the syndrome(s). Dysregulated nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling, driven by comorbidities and ageing, may be the fundamental abnormality in HFpEF, resulting in a systemic inflammatory state and microvascular endothelial dysfunction. Novel informatics platforms are also being used to classify HFpEF into subphenotypes, based on statistically clustered clinical and biological characteristics: whether such subclassification will lead to more targeted therapies remains to be seen. In this review, we summarise current concepts and controversies, and highlight the diagnostic and therapeutic challenges in clinical practice. Novel treatments and disease management strategies are discussed, and the large gaps in our knowledge identified.
Right ventricular recovery during follow-up is associated with improved survival in patients with chronic heart failure with reduced ejection fraction.
Dini Frank Lloyd,Carluccio Erberto,Simioniuc Anca,Biagioli Paolo,Reboldi Gianpaolo,Galeotti Gian Giacomo,Raineri Claudia,Gargani Luna,Scelsi Laura,Mandoli Giulia Elena,Cannito Antonia,Rossi Andrea,Temporelli Pier Luigi,Ghio Stefano,
European journal of heart failure
AIMS:A compromised tricuspid annular plane systolic excursion (TAPSE) is associated with worse survival in patients with chronic heart failure with reduced ejection fraction (HFrEF). However, it is not known whether a reversible abnormal TAPSE at follow-up predicts survival. Our aim was to evaluate whether a reversible abnormal TAPSE is associated with a better survival in patients with chronic HFrEF. METHODS AND RESULTS:A complete echocardiography was performed in 706 patients with chronic HFrEF (LVEF ≤45%) at baseline and after 6 ± 3 months. Right ventricular (RV) systolic function was evaluated using TAPSE. The study endpoint was all-cause mortality. At baseline, TAPSE was severely reduced (≤14 mm) in 89 (13%) patients, and slightly reduced (>14 but <18 mm) in 157 (22%) patients. During a median follow-up of 40 months, 152 patients reached the endpoint. The event rate (per 100 patients/year) was lower in patients with persistently normal TAPSE (≥18 mm, n = 393) [3.3%, 95% confidence interval (CI) 2.5-4.3], and in those with reversible TAPSE (n = 120) (4.6%, 95% CI 3.1-7.0), compared with patients with worsening TAPSE (n = 90) (11.9%, 95% CI 8.7-16.3), and those with persistently reduced TAPSE (n = 103) (12.6%, 95% CI 9.3-17.1; log-rank 69.4, P < 0.0001). A reversible abnormal TAPSE was associated with improved survival at multivariable Cox regression analysis (hazard ratio 0.48, 95% CI 0.29-0.79, P = 0.004). CONCLUSIONS:Patients with chronic HFrEF who have abnormal TAPSE at baseline but reverse their dysfunction during follow-up have better survival than patients with either worsened TAPSE or persistently abnormal TAPSE, and similar to that of patients with persistently normal TAPSE.
Longitudinal evaluation of ventricular ejection fraction and NT-proBNP across heart failure subgroups.
Martinsson Andreas,Oest Petter,Wiborg Maj-Britt,Reitan Öyvind,Smith J Gustav
Scandinavian cardiovascular journal : SCJ
OBJECTIVES:Left ventricular ejection fraction (EF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are important surrogate markers of cardiac function and wall stress. Randomized trials of heart failure (HF) have shown improvements in survival in patients with reduced EF (<40%, HFrEF) but not with preserved EF (≥50%, HFpEF) or mid-range EF (40-49%, HFmrEF). Limited information is available on the trajectory of EF in contemporary heart failure management programs (HFMPs). DESIGN:201 HF patients consecutively enrolled 2010-2011 in the outpatient-based HFMP of Skåne University Hospital in Lund were included in the study. Probable etiology, EF, NT-proBNP and medications were assessed at baseline and 1 year after enrollment. RESULTS:HFrEF was the most common heart failure subgroup (78.1% of patients) in this HFMP, followed by HFmrEF (14.9%) and HFpEF (7.0%). The most common etiology was ischemic heart disease (IHD, 40.8%). Complete recovery of EF (>50%) was rare (14.1% of patients with HFrEF and 26.7% with HFmrEF), some degree of improvement was observed in 57.7% and 46.7% of patients. LVEF improved on average 9.1% in patients with HFrEF (p < .001) and NT-proBNP decreased from 4,202 to 2,030 pg/ml (p < .001). A similar trend was noticed for the HFmrEF group but was not statistically significant. The improvement in LVEF was consistent across subgroups with HF attributable to IHD (6.2%), idiopathic dilated cardiomyopathy (7.1%) and tachycardia-induced HF (17.5%). CONCLUSIONS:This study provides estimates of the improvement in LVEF and NT-proBNP that can be expected with contemporary management across subgroups of HF and different etiologies in a contemporary HFMP.
Detailed Echocardiographic Phenotyping in Breast Cancer Patients: Associations With Ejection Fraction Decline, Recovery, and Heart Failure Symptoms Over 3 Years of Follow-Up.
Narayan Hari K,Finkelman Brian,French Benjamin,Plappert Theodore,Hyman David,Smith Amanda M,Margulies Kenneth B,Ky Bonnie
BACKGROUND:Cardiovascular disease in patients with breast cancer is of growing concern. The longitudinal effects of commonly used therapies, including doxorubicin and trastuzumab, on cardiac remodeling and function remain unknown in this population. We aimed to define the changes in echocardiographic parameters of structure, function, and ventricular-arterial coupling, and their associations with left ventricular ejection fraction (LVEF) and heart failure symptoms. METHODS:In a longitudinal prospective cohort study of 277 breast cancer participants receiving doxorubicin (Dox), trastuzumab (Tras), or both (Dox+Tras), we obtained 1249 echocardiograms over a median follow-up of 2.0 (interquartile range, 1.0-3.0) years. Left ventricular structure, diastolic and contractile function, and ventricular-arterial coupling measures were quantified in a core laboratory blinded to participant characteristics. We evaluated changes in echocardiographic parameters over time, and used repeated-measures regression models to define their association with LVEF decline and recovery. Linear regression models defined the association between early changes in these parameters and subsequent changes in LVEF and heart failure symptoms. RESULTS:Overall, 177 (64%) received Dox, 51 (18%) received Tras, and 49 (18%) received Dox+Tras. With Dox, there was a sustained, modest decrease in LVEF over the follow-up duration (1-year change in LVEF -3.6%; 95% confidence interval [CI], -4.4% to -2.8%; 3-year change -3.8%; 95% CI, -5.1% to -2.5%). With Tras, a similar LVEF decline was observed at 1 year (-4.5%; 95% CI, -6.0% to -2.9%) and 3 years (-2.8%; 95%CI, -5.3 to -0.4%). Participants receiving Dox+Tras demonstrated the greatest declines at 1 year (-6.6%; 95% CI, -8.2 to -5.0%), with partial recovery at 3 years (-2.8%; 95% CI, -4.8 to -0.8%). LVEF declines and recovery were associated primarily with changes in systolic volumes, longitudinal and circumferential strain, and ventricular-arterial coupling indices, effective arterial elastance (Ea) and the coupling ratio Ea/Ees, without evidence for effect modification across therapies. Early changes in volumes, strain, and Ea/Ees at 4 to 6 months were associated with 1- and 2-year LVEF changes. Similarly, early changes in strain and Ea were associated with worsening heart failure symptoms at 1 year. CONCLUSIONS:Doxorubicin and trastuzumab resulted in modest, persistent declines in LVEF at 3 years. Changes in volumes, strain, and ventricular-arterial coupling were consistently associated with concurrent and subsequent LVEF declines and recovery across therapies.
Heart Failure and Midrange Ejection Fraction: Implications of Recovered Ejection Fraction for Exercise Tolerance and Outcomes.
Nadruz Wilson,West Erin,Santos Mário,Skali Hicham,Groarke John D,Forman Daniel E,Shah Amil M
Circulation. Heart failure
BACKGROUND:Evidence-based therapies for heart failure (HF) differ significantly according to left ventricular ejection fraction (LVEF). However, few data are available on the phenotype and prognosis of patients with HF with midrange LVEF of 40% to 55%, and the impact of recovered systolic function on the clinical features, functional capacity, and outcomes of this population is not known. METHODS AND RESULTS:We studied 944 patients with HF who underwent clinically indicated cardiopulmonary exercise testing. The study population was categorized according to LVEF as follows: HF with reduced LVEF (HFrEF; LVEF<40%; n=620); HF with midrange ejection fraction and no recovered ejection fraction (LVEF was consistent between 40% and 55%; n=107); HF with recovered midrange ejection fraction (LVEF, 40%-55% but previous LVEF<40%; n=170); and HF with preserved LVEF (HFpEF; LVEF>55%; n=47). HF with midrange ejection fraction and no recovered ejection fraction and HF with recovered midrange ejection fraction had similar clinical characteristics, which were intermediate between those of HFrEF and HFpEF, and comparable values of predicted peak oxygen consumption and minute-ventilation/carbon dioxide production slope, which were better than HFrEF and similar to HFpEF. After a median of 4.4 (2.9-5.7) years, there were 253 composite events (death, left ventricular assistant device implantation, or transplantation). In multivariable Cox-regression analysis, HF with recovered midrange ejection fraction had lower risk of composite events than HFrEF (hazard ratio, 0.25; 95% confidence interval, 0.13-0.47) and HF with midrange ejection fraction and no recovered ejection fraction (hazard ratio, 0.31; 95% confidence interval, 0.15-0.67), and similar prognosis when compared with HFpEF. In contrast, HF with midrange ejection fraction and no recovered ejection fraction tended to show intermediate risk of outcomes in comparison with HFpEF and HFrEF, albeit not reaching statistical significance in fully adjusted analyses. CONCLUSIONS:Patients with HF with midrange LVEF demonstrate a distinct clinical profile from HFpEF and HFrEF patients, with objective measures of functional capacity similar to HFpEF. Within the midrange LVEF HF population, recovered systolic function is a marker of more favorable prognosis.
Importance of baseline heart rate as a predictor of cardiac functional recovery in newly diagnosed heart failure with reduced ejection fraction.
Valika Ali,Paprockas Kim,Villines Dana,Costanzo Maria Rosa
BACKGROUND:Left ventricular ejection fraction (LVEF) has shown to predict outcomes in patients with heart failure (HF). Left ventricular recovery (LVR) has shown to improve prognosis. HYPOTHESIS:Guideline-directed medical therapy will predict LVR in patients with HF and reduced LVEF. METHODS:We studied 244 patients with newly diagnosed HF and an LVEF ≤35%. LVR was defined as an increase in LVEF ≥40%. Patients who experienced LVR were compared with those who had persistent left ventricular dysfunction. RESULTS:Population characteristics included ischemic etiology, 38.1%; baseline LVEF, 23% ±6%; and mean baseline heart rate (HR), 75 ±13 bpm. Guideline-directed medical therapy was achieved as follows: angiotensin-converting enzyme inhibitors, 74.3%; β-blockers (BB), 95.4%; target dosing of angiotensin-converting enzyme inhibitors, 33.7%; target dosing of BB, 40.2%. LVR occurred in 154/244 patients (63.1%). By multivariable analysis, baseline HR ≤70 bpm was the only independent predictor of LVR (odds ratio: 3.39, 95% confidence interval: 1.5-7.5, P = 0.003). Target dosing of BB therapy was predictive of LVR only in the univariate analysis (odds ratio: 1.9, 95% confidence interval: 1.1-3.4, P = 0.03). Furthermore, the composite endpoint of HF hospitalization or mortality occurred less frequently in those who did vs those who did not achieve target BB doses (5.4% vs 16.7%, respectively; P = 0.023). CONCLUSIONS:The novel findings of our analysis reveal that the only predictor of LVR in this study was a low baseline HR. Early modulation of HR in newly diagnosed HF patients may increase the rates of LVR.
Angiotensin Receptor Neprilysin Inhibitor for Patients With Heart Failure and Reduced Ejection Fraction: Real-World Experience From Taiwan.
Hsiao Fu-Chih,Wang Chun-Li,Chang Po-Cheng,Lu Yu-Ying,Huang Chien-Ying,Chu Pao-Hsien
Journal of cardiovascular pharmacology and therapeutics
BACKGROUND:Angiotensin receptor neprilysin inhibitor (ARNI) was recommended by major guidelines as the frontline therapy for heart failure with reduced ejection fraction (HFrEF) since its clinical benefit was proved in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial. However, little is known about its safety and effectiveness in real-world practice, often with sicker and more fragile patients. In addition, East Asia population is underrepresented in PARADIGM-HF trial. METHODS:We performed a retrospective analysis of patients who received ARNI in 3 medical institutes located in Northern Taiwan. Patients who received a prescription of at least 30 days of ARNI were enrolled. The date of first prescription was defined as the index date, and a period of 12 months preceding the index date was defined as the baseline period. RESULTS:A total of 452 patients were identified (age: 61.9 ± 15.0, male: 79.4%). Compared to PARADIGM-HF populations, our patients had higher values of baseline serum creatinine (mean: 1.5 vs 1.1 mg/dL) and B-type natriuretic peptide (BNP; median: 554.5 vs 255 pg/mL). After 12 months, 41.6% of the patients received less than half of the standard dose. Overall, all-cause death, cardiovascular death, and heart failure readmission rate were 3.0%, 1.1%, and 6.9% in 12 months, respectively. In those who had both baseline and 12-month data, renal function did not change (1.7-1.8 mg/dL, = .091), left ventricular ejection fraction improved (30.8%-36.8%, < .001), BNP decreased (777.0-655.8 pg/mL, = .032), and uric acid decreased (7.5-7.1 mg/dL, = .009). CONCLUSION:In our study, patients with HFrEF had higher BNP and serum creatinine level at baseline and had received lower dose of ARNI than the PARADIGM-HF populations. Angiotensin receptor neprilysin inhibitor appeared to be safe as regard renal function and effective in real-world practice. Left ventricular reverse remodeling was observed 1 year after heart failure medication treatment, including ARNI.
IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction.
Van Tassell Benjamin W,Trankle Cory R,Canada Justin M,Carbone Salvatore,Buckley Leo,Kadariya Dinesh,Del Buono Marco G,Billingsley Hayley,Wohlford George,Viscusi Michele,Oddi-Erdle Claudia,Abouzaki Nayef A,Dixon Dave,Biondi-Zoccai Giuseppe,Arena Ross,Abbate Antonio
Circulation. Heart failure
Background Enhanced inflammation may lead to exercise intolerance in heart failure with preserved ejection fraction. The aim of the current study was to determine whether IL (interleukin)-1 blockade with anakinra improved cardiorespiratory fitness in heart failure with preserved ejection fraction. Methods and Results Thirty-one patients with heart failure with preserved ejection fraction and CRP (C-reactive protein) >2 mg/L were randomized to anakinra (100 mg subcutaneously daily, N=21) or placebo (N=10) for 12 weeks. We measured peak oxygen consumption (Vo), ventilatory efficiency (V/Vco slope), and high-sensitivity CRP and NT-proBNP (N-terminal pro-B-type natriuretic peptide) at 4, 12, and 24 weeks. Twenty-eight patients completed ≥2 visits, 18 women (64%), 27 (96%) obese. There were no differences in peak Vo or V/Vco slope between groups at baseline. Peak Vo was not changed after 12 weeks of anakinra (from 13.6 [11.8-18.0] to 14.2 [11.2-18.5] mL·kg·min, P=0.89), or placebo (14.9 [11.7-17.2] to 15.0 [13.8-16.9] mL·kg·min, P=0.40), without significant between-group differences in changes at 12 weeks (-0.4 [95% CI, -2.2 to +1.4], P=0.64). V/Vco slope was also unchanged with anakinra (from 28.3 [27.2-33.0] to 30.5 [26.3-32.8], P=0.97) or placebo (from 31.6 [27.3-36.9] to 31.2 [27.8-33.4], P=0.78), without significant between-group differences in changes at 12 weeks (+1.2 [95% CI, -1.8 to +4.3], P=0.97). Within the anakinra-treated patients, high-sensitivity CRP and NT-proBNP levels were lower at 4 weeks compared with baseline ( P=0.026 and P=0.022 versus placebo [between-group analysis], respectively). Conclusions Treatment with anakinra for 12 weeks failed to improve peak Vo and V/Vco slope in a group of obese heart failure with preserved ejection fraction patients. The favorable trends in high-sensitivity CRP and NT-proBNP with anakinra deserve exploration in future studies. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02173548.
Heart failure with recovered ejection fraction: Clinical characteristics, determinants and prognosis. CARDIOCHUS-CHOP registry.
Agra Bermejo Rosa,Gonzalez Babarro Eva,López Canoa J Nicolás,Varela Román Alfonso,Gómez Otero Inés,Oro Ayude Marcos,Parada Vazquez Pablo,Gómez Rodríguez Isabel,Díaz Castro Oscar,González Juanatey Jose Ramón
BACKGROUND:The magnitude and the prognostic impact of recovering left ventricular ejection fraction (LVEF) in patients with heart failure (HF) and systolic dysfunction is unclear. The aim of this study was to evaluate the clinical characteristics and prognosis of patients with HFrecEF in an HF population. METHODS:449 consecutive patients were selected with the diagnosis of HF and an evaluation of LVEF in the 6 months prior to selection who were referred to two HF units. Patients with systolic dysfunction were only considered if a second echocardiogram was performed during the follow-up. RESULTS:At the time of diagnosis, 207 patients had LVEF > 40% (HFpEF) and 242 had LVEF ≤ 40% (HFrEF). After 1 year, the LVEF was re-evaluated in all 242 patients with a LVEF ≤ 40%: in 126 (52%), the second LVEF was > 40% (HFrecEF), and the remaining 116 (48%) had LVEF ≤ 40% (HFrEF). After 1800 ± 900 days of follow-up patients with recovered LVEF had a significantly lower mortality rate (HFpEF vs. HFrecEF: hazard ratio [HR] = 2.286, 95% confidence interval [95% CI] 1.264-4.145, p = 0.019; HFrEF vs. HFrecEF: HR = 2.222, 95% CI 1.189-4.186, p < 0.001) and hospitalization rate (HFpEF vs. HFrecEF: HR = 1.411, 95% CI 1.046-1.903, p = 0.024; HFrEF vs. HFrecEF: HR = 1.388, 95% CI 1.002-1.924, p = 0.049). The following are predictors of LVEF recovery: younger age, lower functional class, treatment with renin-angiotensin-aldosterone system inhibitors and beta-blockers, absence of defibrillator use, and non-ischemic etiology. CONCLUSIONS:Patients with HF and reduced LVEF who were re-evaluated after 1 year, had significant improvement in their LVEF and had a more favourable prognosis than HF with preserved and reduced ejection fraction.
Epidemiology of "Heart Failure with Recovered Ejection Fraction": What do we do After Recovery?
Kuttab Johny S,Kiernan Michael S,Vest Amanda R
Current heart failure reports
Improvement in functional status, long-term survival, and quality of life has always been the goal of therapy in patients with heart failure with reduced ejection fraction. Neurohormonal modulating medications help patients achieve these goals and, in a subgroup of patients, can promote "reverse remodeling" resulting in the recovery of left ventricular systolic function. In the era of durable mechanical support, myocardial recovery that leads to explantation of the ventricular assist device occurs in a minority of cases. Optimal medical therapy appears to be a key component of achieving myocardial recovery, with recovery more likely in patients with a shorter duration of heart failure and a non-ischemic etiology. However, little is known about future management of patients who attain myocardial recovery, either with or without mechanical support. This review explores the epidemiology, physiology, cellular biology, and long-term outcomes for this subgroup of heart failure patients and outlines areas for future study.
Characteristics, Outcomes, and Treatment of Heart Failure With Improved Ejection Fraction.
Park Chan Soon,Park Jin Joo,Mebazaa Alexandre,Oh Il-Young,Park Hyun-Ah,Cho Hyun-Jai,Lee Hae-Young,Kim Kye Hun,Yoo Byung-Su,Kang Seok-Min,Baek Sang Hong,Jeon Eun-Seok,Kim Jae-Joong,Cho Myeong-Chan,Chae Shung Chull,Oh Byung-Hee,Choi Dong-Ju
Journal of the American Heart Association
Background Many patients with heart failure ( HF ) with reduced ejection fraction ( HF r EF ) experience improvement or recovery of left ventricular ejection fraction ( LVEF ). Data on clinical characteristics, outcomes, and medical therapy in patients with HF with improved ejection fraction (HFiEF) are scarce. Methods and Results Of 5625 consecutive patients hospitalized for acute HF in the KorAHF (Registry [Prospective Cohort] for Heart Failure in Korea) study, 5103 patients had baseline echocardiography and 2302 patients had follow-up echocardiography at 12 months. HF phenotypes were defined as persistent HF r EF ( LVEF ≤40% at baseline and at 1-year follow-up), HF i EF ( LVEF ≤40% at baseline and improved up to 40% at 1-year follow-up), HF with midrange ejection fraction (LVEF between 40% and <50%), and HF with preserved ejection fraction ( LVEF ≥50%). The primary outcome was 4-year all-cause mortality from the time of HF i EF diagnosis. Among 1509 HF r EF patients who had echocardiography 1 year after index hospitalization, 720 (31.3%) were diagnosed as having HF i EF . Younger age, female sex, de novo HF , hypertension, atrial fibrillation, and β-blocker use were positive predictors and diabetes mellitus and ischemic heart disease were negative predictors of HF i EF . During 4-year follow-up, patients with HF i EF showed lower mortality than those with persistent HF r EF in univariate, multivariate, and propensity-score-matched analyses. β-Blockers, but not renin-angiotensin system inhibitors or mineralocorticoid receptor antagonists, were associated with a reduced all-cause mortality risk (hazard ratio: 0.59; 95% CI , 0.40-0.87; P=0.007). Benefits for outcome seemed similar among patients receiving low- or high-dose β-blockers (log-rank, P=0.304). Conclusions HF i EF is a distinct HF phenotype with better clinical outcomes than other phenotypes. The use of β-blockers may be beneficial for these patients. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT01389843.
Heart Failure With Improved Ejection Fraction: Is it Possible to Escape One's Past?
Gulati Gaurav,Udelson James E
JACC. Heart failure
Among patients with heart failure with reduced ejection fraction, investigators have repeatedly identified a subgroup whose left ventricular ejection fraction and structural remodeling can improve to normal or nearly normal levels with or without medical therapy. This subgroup of patients with "heart failure with improved ejection fraction" has distinct clinical characteristics and a more favorable prognosis compared with patients who continue to have reduced ejection fraction. However, many of these patients also manifest clinical and biochemical signs of incomplete resolution of heart failure pathophysiology and remain at some risk of adverse outcomes, thus indicating that they may not have completely recovered. Although rigorous evidence on managing these patients is sparse, there are several reasons to recommend continuation of heart failure therapies, including device therapies, to prevent clinical deterioration. Notable exceptions to this recommendation may include patients who recover from peripartum cardiomyopathy, fulminant myocarditis, or stress cardiomyopathy, whose excellent long-term prognoses may imply true myocardial recovery. More research on these patients is needed to better understand the mechanisms that lead to improvement in ejection fraction and to guide their clinical management.
Heart Failure With Recovered Ejection Fraction in African Americans: Results From the African-American Heart Failure Trial.
Chang Kay-Won,Beri Neil,Nguyen Nghia H,Arbit Boris,Fox Sutton,Mojaver Sean,Clopton Paul,Tam S William,Taylor Anne L,Cohn Jay N,Maisel Alan S,Anand Inder S
Journal of cardiac failure
BACKGROUND:Recent studies have described the entity of heart failure with recovered ejection fraction (HFrecEF), but population-specific studies remain lacking. The aim of this study was to characterize patients enrolled in the African-American Heart Failure Trial (A-HeFT) who had significant improvement in their ejection fraction (EF) during the 1st 6 months of follow-up. METHODS AND RESULTS:Subjects with HFrecEF (improvement in EF from <35% to >40% in 6 months; n = 59) were compared with 259 subjects with heart failure and persistently reduced EF (HFrEF), defined as EF ≤40% at 6-month follow-up. The effects of improvement in EF on all-cause mortality and 1st and all hospitalizations were analyzed. Compared with HFrEF, subjects with HFrecEF had a nonsignificant trend toward lower mortality (hazard ratio [HR] 0.16, 95% confidence interval [CI] 0.02-1.15; P = .068), fewer 1st HF hospitalizations (HR 0.22, 95% CI 0.07-0.71; P = .011), fewer recurrent HF hospitalizations (HR 0.13, 95% CI 0.05-0.37; P <.001), similar 1st all-cause hospitalizations (HR 0.67, 95% CI 0.39-1.15; P = .150), and fewer recurrent all-cause hospitalizations (HR 0.41, 95% CI 0.24-0.68; P <.001). CONCLUSIONS:These data confirm that, as in other populations, a small subgroup of black patients receiving standard care improve their EF with favorable outcomes. Further studies are required to determine whether myocardial recovery is permanent and the best management strategies in such patients.
Heart Failure With Improved Ejection Fraction: Clinical Characteristics, Correlates of Recovery, and Survival: Results From the Valsartan Heart Failure Trial.
Florea Viorel G,Rector Thomas S,Anand Inder S,Cohn Jay N
Circulation. Heart failure
BACKGROUND:Heart failure with recovered or improved ejection fraction (HFiEF) has been proposed as a new category of HF. Whether HFiEF is clinically distinct from HF with persistently reduced ejection fraction remains to be validated. METHODS AND RESULTS:Of the 5010 subjects enrolled in the Valsartan Heart Failure Trial (Val-HeFT), 3519 had a baseline left ventricular EF of <35% and a follow-up echocardiographic assessment of EF at 12 months. Of these, 321 (9.1%) patients who had a 12-month EF of >40% constituted the subgroup with HFiEF. EF improved from 28.7±5.6% to 46.5±5.6% in the subgroup with HFiEF and remained reduced (25.2±6.2% and 27.5±7.1%) in the subgroup with HF with reduced ejection fraction. The group with HFiEF had a less severe hemodynamic, biomarker, and neurohormonal profile, and it was treated with a more intense HF medication regimen. Subjects who had higher blood pressure and those treated with a β-blocker or randomized to valsartan had greater odds of being in the HFiEF group, whereas those with an ischemic pathogenesis, a more dilated left ventricle, and a detectable hs-troponin had lower odds of an improvement in EF. Recovery of the EF to >40% was associated with a better survival compared with persistently reduced EF. CONCLUSIONS:Our data support HFiEF as a stratum of HF with reduced ejection fraction with a more favorable outcome, which occurs in a minority of patients with HF with reduced ejection fraction who have a lower prevalence of ischemic heart disease, a less severe hemodynamic, biomarker, and neurohormonal profile, and who are treated with a more intense HF medication regimen. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336.
Heterogeneous Outcomes of Heart Failure with Better Ejection Fraction.
Van Kirk Jenny,Fudim Marat,Green Cynthia L,Karra Ravi
Journal of cardiovascular translational research
We evaluated the heterogeneity of outcomes among heart failure patients with ventricular recovery. The BEST trial studied patients with left ventricular ejection fraction (LVEF) ≤ 35%. Serial LVEF assessment was performed at baseline, 3 months, and 12 months. Heart failure with better ejection fraction (HFbEF) was defined as an LVEF > 40% at any point. Of the patients who survived to 1 year, 399 (21.3%) had HFbEF. Among subjects with HFbEF, 173 (43.4%) had "extended" recovery, 161 (40.4%) had "late" recovery, and 65 (16.3%) patients had "transient" recovery. Subjects with HFbEF had an improved event-free survival from death or first HF hospitalization compared to subjects without recovery (HR 0.50, 95% CI, 0.39-0.64, p < 0.001). Compared to "transient" recovery, "late" and "extended" recovery were associated with an improved event-free survival from all-cause death and HF hospitalization (HR 0.55, 95% CI, 0.34-0.90, p = 0.016). Our study shows patients with HFbEF to be a heterogeneous population with differing prognoses.
Association of Genetic Polymorphisms in the Beta-1 Adrenergic Receptor with Recovery of Left Ventricular Ejection Fraction in Patients with Heart Failure.
Luzum Jasmine A,English Joseph D,Ahmad Umair S,Sun Jessie W,Canan Benjamin D,Sadee Wolfgang,Kitzmiller Joseph P,Binkley Philip F
Journal of cardiovascular translational research
Two common genetic polymorphisms in the beta-1 adrenergic receptor (ADRB1 Ser49Gly [rs1801252] and Arg389Gly [rs1801253]) significantly affect receptor function in vitro. The objective of this study was to determine whether ADRB1 Ser49Gly and Arg389Gly are associated with recovery of left ventricular ejection fraction (LVEF) in patients with heart failure. Patients with heart failure and baseline LVEF ≤ 40% were genotyped (n = 98), and retrospective chart review assessed the primary outcome of LVEF recovery to ≥ 40%. Un/adjusted logistic regression models revealed that Ser49Gly, but not Arg389Gly, was significantly associated with LVEF recovery in a dominant genetic model. The adjusted odds ratio for Ser49 was 8.2 (95% CI = 2.1-32.9; p = 0.003), and it was the strongest predictor of LVEF recovery among multiple clinical variables. In conclusion, patients with heart failure and reduced ejection fraction that are homozygous for ADRB1 Ser49 were significantly more likely to experience LVEF recovery than Gly49 carriers.