Kansas City Cardiomyopathy Questionnaire Score Research Articles

Abstract 11974: A Randomized, Controlled Trial of Resistance Training Added to Caloric Restriction Plus Aerobic Exercise Training in Obese Heart Failure With Preserved Ejection Fraction

Background: We previously showed that the combination of caloric restriction (CR) and aerobic exercise training (AT) produce robust improvements in exercise capacity and quality of life (QOL) in patients with obese Heart Failure with Preserved Ejection Fraction (HFpEF). However, ~ 35% of weight lost during CR+AT was from skeletal muscle (SM) mass, which may have adverse long-term consequences. Hypothesis: The addition of resistance training (RT) to CR+AT would reduce SM loss and further improve exercise capacity and QOL. Methods: Randomized, controlled, single blind trial of 20 weeks of RT+CR+AT vs. CR+AT in 88 patients with HFpEF and body mass index (BMI) ≥28 kg/m 2 . Measurements were: peak exercise O 2 consumption (VO 2 ); body composition by MRI and dual X-ray absorptiometry; leg muscle strength; leg muscle quality (leg strength ÷ leg SM area); Kansas City Cardiomyopathy Questionnaire (KCCQ) total score. Results: 77 participants completed the trial: age 68±5 years; 85% women; BMI 39.6±5.8 kg/m 2 . Both RT+CR+AT and CR+AT had substantial weight loss, mean (95% CI): -8.1 (-9.3, -6.8) vs. -9.2 (-10.5, -7.9) kg with no significant intergroup difference (p=0.21). Both RT+CR+AT and CR+AT had substantial loss of total body fat [-6.5 (-7.2, -5.8) vs. -7.4 (-8.1, -6.7) kg] and SM [-2.1 (-2.7,- 1.5) vs. -2.1 (-2.7, -1.4) kg], with no intergroup differences (p=0.20 and 0.23, respectively). Despite similar relative loss of SM (26% vs. 23% of total weight lost), RT+CR+AT vs. CR+AT alone produced significantly greater increases in leg muscle strength [4.9 (0.7, 9.0) vs. -1.1 (-5.5, 3.2) Nm, p=0.05] and leg muscle quality [0.07 (0.03, 0.11) vs. 0.02 (-0.02, 0.06) Nm/cm 2 , p=0.04]. Both RT+CR+AT and CR+AT produced large, significant improvements in peak VO 2 [108 (958, 157) vs. 80 (30, 130) ml/min; p=0.001 and 0.002, respectively], and in KCCQ score [17 (12, 22) vs. 23 (17, 28); p=0.001 for both], with no significant intergroup differences (p=0.21 and p=0.07, respectively). There were no study related serious adverse events. Conclusion: In older obese HFpEF patients, CR+AT produces large, significant improvements in exercise capacity and QOL. Addition of RT to CR+AT increased leg strength and leg muscle quality without attenuating SM loss or further increasing peak VO 2 or KCCQ score.

Abstract 10733: Health Status Outcomes by Race in Patients Treated With Sodium-Glucose Cotransporter 2 Inhibitors: A Pooled Patient-Level Meta-Analysis of CHIEF-HF, DEFINE-HF, and PRESERVED-HF

Introduction Black patients with heart failure (HF) have worse health status (symptoms, function, and quality of life) compared with White patients. Reducing this disparity is a national priority. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) not only improve cardiovascular mortality and hospitalization rates in HF patients regardless of ejection fraction (EF) but also improve patients’ health status. However, because Black patients have not been well represented in global HF outcomes trials, whether the benefits of SGLT2i on health status are consistent in patients with HF regardless of race is not well understood. Methods We combined patient-level data from three US randomized, double-blinded clinical trials of SGLT2i vs. placebo, DEFINE-HF (n=263), PRESERVED-HF (n=324), and CHIEF-HF (n=448). All three trials collected the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12-weeks after treatment initiation. We assessed the change in the KCCQ clinical summary score (CSS, which comprises symptoms and physical limitations) by treatment arm in White and Black participants and tested the interaction of treatment by race using multivariable linear regression adjusting for trial and baseline KCCQ scores (as a restricted cubic spline). Results Among 935 participants, 236 (25%) self-identified as Black, and 469 (50.2%) were treated with an SGLT2i. Treatment-related changes in the KCCQ by race are summarized in the Table. Treatment with an SGLT2i vs. placebo resulted in 4.7-point improvement in CCS in Black patients (95% CI 0.74, 8.68; p= 0.02) and 4-point improvement in White patients (95% CI 1.69, 6.29; p=0.0007), with no treatment benefit heterogeneity by race (interaction p-value = 0.76). Conclusions The health status benefits of SGLT2i are consistent in Black and White patients. Therefore, whether improved access to SGLT2i can reduce HF-related health status disparities in Black patients should be tested.

Sex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVER.

Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin. In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction. Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (Pinteraction=0.77) with no sex-related differences in secondary outcomes (all Pinteraction>0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex (Pinteraction>0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events. In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

Characteristics of symptoms and symptom change across different heart failure subtypes: a sex-stratified analysis.

To examine sex-stratified differences in the association of left ventricular ejection fraction-based heart failure (HF) subtypes and the characteristics and correlates of self-reported changes in HF symptoms. We report a secondary data analysis from 528 hospitalized individuals diagnosed with HF characterised by a reduced, mildly reduced, or preserved ejection fraction [HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), or HF with preserved ejection fraction (HFpEF)] who completed 12-month follow-up within a multicentre disease management trial. There were 302 men (71.1 ± 11.9 years, 58% with HFrEF) and 226 women (77.1 ± 10.6 years, 49% with HFpEF). The characteristics of self-reported symptoms measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12-month were analysed. At baseline, shortness of breath and fatigue predominated; with key differences according to HF subtypes in bilateral ankle oedema (both sexes), walking problems (women) and depressive symptoms (men). At 12-month follow-up, most KCCQ scores had not significantly changed. However, 25% of individuals reported worse symptom. In women, those with HFpEF had worse symptoms than those with HFmrEF/HFrEF (P = 0.025). On an adjusted basis, women [odds ratios (OR): 1.78, 95% confidence interval (CI): 1.00-3.16 vs. men], those with coronary artery disease (OR: 2.01, 95% CI: 1.21-3.31) and baseline acute pulmonary oedema (OR: 1.67, 95% CI: 1.02-2.75) were most likely to report worsening symptoms. Among men, worsening symptoms correlated with a history of hypertension (OR: 2.16, 95% CI: 1.07-4.35) and a non-English-speaking background (OR: 2.30, 95% CI: 1.02-5.20). We found significant heterogeneity (with potential clinical implications) in the symptomatic characteristics and subsequent symptom trajectory according to the sex and HF subtype of those hospitalized with the syndrome. ANZCTR12613000921785.

Long-term Outcomes of Transcatheter Aortic Valve Replacement With the Lotus Valve vs CoreValve/EvolutR

Long-term follow-up after transcatheter aortic valve replacement (TAVR) is of interest given that longitudinal data on mortality and durability of transcatheter heart valves are limited. The REPRISE III (Repositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus Valve System-Randomized Clinical Evaluation) randomized clinical trial compared the mechanically expanded Lotus valve with the self-expanding CoreValve/EvolutR TAVR platforms. To describe the final 5-year outcomes of the REPRISE III trial. This prespecified secondary analysis assessed the final 5-year clinical, functional, and echocardiographic outcomes of 912 patients from the REPRISE III trial, which was conducted at 55 centers in North America, Europe, and Australia between September 22, 2014, and December 24, 2015. Patients had high risk for aortic stenosis or severe or symptomatic aortic stenosis. Data were analyzed from September 22, 2014, to May 21, 2021. Lotus valve or CoreValve/EvolutR TAVR platforms. Valve Academic Research Consortium-2 end points, hemodynamic measures, functional status, and health status were examined through the 5-year follow-up. A total of 912 patients (mean [SD] age, 82.8 [7.3] years; 463 women [50.8%]) were randomized to either the Lotus valve group (n = 607) or CoreValve/EvolutR group (n = 305), with a baseline Society of Thoracic Surgeons risk score of 6.8%. Clinical follow-up data from the REPRISE III trial were available for 581 patients (95.7%) in the Lotus valve group and 285 patients (93.4%) in the CoreValve/EvolutR group. At 5 years, the cumulative event rate for all-cause mortality was 50.9% in the Lotus valve group vs 52.8% in the CoreValve/EvolutR group (P = .59). Disabling stroke was less frequent with the Lotus valve vs CoreValve/EvolutR (cumulative event rates, 8.3% vs 12.2%; P = .04), whereas the cumulative event rates for overall stroke were similar in both groups (14.1% vs 15.3%; P = .38). Insertion of a new permanent pacemaker (38.9% vs 27.3%; P < .001) and detection of prosthetic aortic valve thrombosis (5.8% vs 1.8%; P = .007) were more common in the Lotus valve group than in the CoreValve/EvolutR group. A smaller proportion of patients who received the Lotus valve experienced valve malpositioning (0% vs 2.6%; P < .001) and required the use of a second valve (1.0% vs 3.8%; P < .001) during the procedure compared with those who received the CoreValve/EvolutR. Compared with the Lotus valve group, the CoreValve/EvolutR group had a significantly lower mean (SD) aortic gradient (7.8 [4.2] mm Hg vs 12.6 [6.7] mm Hg; P < .001) and larger valve areas (1.57 [0.56] cm2 vs 1.42 [0.42] cm2; P = .10). After 5 years, the proportion of patients with moderate or greater paravalvular leak was not significantly higher with the CoreValve/EvolutR than with the Lotus valve (1.9% vs 0%; P = .31); however, the proportion of patients with mild paravalvular leak was higher in the CoreValve/EvolutR group compared with the Lotus valve group (23.1% vs 7.8%; P = .006). Long-term, similar improvements in New York Heart Association class and Kansas City Cardiomyopathy Questionnaire score were observed in both groups. The REPRISE III trial found that, at 5 years, the clinical outcomes of the Lotus valve were comparable to those of the CoreValve/EvolutR and that the Lotus valve was safe and effective. ClinicalTrials.gov Identifier: NCT02202434.

Association of epicardial adipose tissue with proteomics, coronary flow reserve, cardiac structure and function, and quality of life in heart failure with preserved ejection fraction: insights from the PROMIS-HFpEF study.

Epicardial adipose tissue (EAT) may play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We investigated associations of EAT with proteomics, coronary flow reserve (CFR), cardiac structure and function, and quality of life (QoL) in the prospective multinational PROMIS-HFpEF cohort. Epicardial adipose tissue was measured by echocardiography in 182 patients and defined as increased if ≥9 mm. Proteins were measured using high-throughput proximity extension assays. Microvascular dysfunction was evaluated with Doppler-based CFR, cardiac structural and functional indices with echocardiography and QoL by Kansas City Cardiomyopathy Questionnaire (KCCQ). Patients with increased EAT (n=54; 30%) had higher body mass index (32 [28-40] vs. 27 [23-30] kg/m2 ; p < 0.001), lower N-terminal pro-B-type natriuretic peptide (466 [193-1133] vs. 1120 [494-1990] pg/ml; p < 0.001), smaller indexed left ventricular (LV) end-diastolic and left atrial (LA) volumes and tendency to lower KCCQ score. Non-indexed LV/LA volumes did not differ between groups. When adjusted for body mass index, EAT remained associated with LV septal wall thickness (coefficient 1.02, 95% confidence interval [CI] 1.00-1.04; p=0.018) and mitral E wave deceleration time (coefficient 1.03, 95% CI 1.01-1.05; p=0.005). Increased EAT was associated with proteomic markers of adipose biology and inflammation, insulin resistance, endothelial dysfunction, and dyslipidaemia but not significantly with CFR. Increased EAT was associated with cardiac structural alterations and proteins expressing adiposity, inflammation, lower insulin sensitivity and endothelial dysfunction related to HFpEF pathology, probably driven by general obesity. Potential local mechanical or paracrine effects mediated by EAT remain to be elucidated.

Transcarotid Versus Transfemoral Transcatheter Aortic Valve Replacement (from a Propensity-Matched Comparison)

Previous reports comparing transcarotid (TC) versus transfemoral (TF) approaches for patients undergoing transcatheter aortic valve replacement have had inconsistent conclusions. We compared in-hospital and 1-year clinical outcomes, changes in quality of life, and direct hospital costs for 138 TC versus 1,926 TF procedures. Propensity matching based on the Society of Thoracic Surgery Predicted Risk of Mortality was used to compare 130 patients who underwent TC with 813 patients who underwent TF. Matched TC versus TF cohorts did not differ with respect to in-hospital mortality (0.0% vs 1.4%, p=0.380), stroke (2.3% vs 2.5%, p=0.917), major vascular complications (0.8% vs 2.2%, p=0.268), composite bleeding complications (4.6% vs 6.4%, p=0.647), requirement for permanent pacemaker (14.6% vs 12.9%, p=0.426), postoperative hospital length of stay (3.3 ± 3.4 vs 3.1 ± 3.3 days, p=0.467), or direct hospital costs ($52,899 ± 9,560 vs $50,464 ± 10,997, p=0.230). Similarly, at 1-year, patients who underwent TC versus patients who underwent TF did not differ with respect to all-cause mortality (7.6% vs 6.4%, p=0.659), hospital readmission (20.0% vs 23.9%, p=0.635), or quality of life as measured by the Kansas City Cardiomyopathy Questionnaire score (84.0 ± 17.1 vs 88.4 ± 13.9, p=0.062). Patients who underwent TC and TF did not differ with respect to in-hospital complications, length of hospital stay, and direct hospital costs, as well as 1-year mortality, readmission, and quality of life. These data add to ongoing support for the TC approach as the optimal alternative access for patients with transcatheter aortic valve replacement deferred from a transfemoral approach.

Transthoracic echocardiography guidance of transcatheter edge-to-edge percutaneous tricuspid valve repair: the TTE-TTVR pilot study and methodology proposal

Abstract Background Transcatheter tricuspid valve repair (TTVR) is an emerging option for treating high-grade tricuspid regurgitation (TR) [1], mostly performed by edge-to-edge repair, and always guided by transesophageal echocardiography (TOE). In patients with excellent acoustic window, transthoracic echocardiography (TTE) can also provide a comprehensive understanding of tricuspid valve (TV) morphology [2]. Also, in TTVR there is no need for transseptal puncture. Purpose We sought to determine if TTVR can be successfully conducted by a novel TTE guiding approach, in conjunction with fluoroscopy [3]. Methods 30 consecutive patients, scheduled for TTVR, were assigned to a TTE group (n=10), in the presence of excellent acoustic window, and a TOE group (n=20). On top of fluoroscopy, TTVR was guided exclusively by TTE in the first group, with TOE result confirmation solely upon clip release, due to safety reasons. The second group underwent classical TOE guidance. Understanding the 4 right heart chamber views (Fig. 1) and their respective fluoroscopic angulations was paramount. TR severity, parameters of quality of life and functional capacity were assessed and compared between-groups, at baseline and 30 days. Results Except for lower BMI (TTE 22.3±0.8 vs TOE 29.8±4.3, p&amp;lt;0.001), other baseline characteristics were very similar between groups, e.g., age (81.7±3.9 vs 82.8±4.1, p=0.483) or EuroSCORE II (11.9±10.3 vs 10.4±8, p=0.692).Device success was achieved in all patients, with a total of 15 implanted clips in the TTE group (mean no. of clips / patient 1.5±0.7) and 31 clips in the TOE group (1.5±0.6). Device time (75±37.1 vs 65.7±31.3 minutes, p=0.506) and fluoroscopy duration (16.3±10.5 vs 14.4±7.2 minutes, p=0.564) were also close. TR reduction was successful in all but one patient, in each group (90% vs 95%, p=1.000). TR improvement was equal between-groups, with 2 or more grade reduction in 60% of each group, at 30 days. Thus, grade IV/V and V/V TR, present in 60% of all patients at baseline, dropped to 10% (9/10 vs 18/20, p=1.000) by procedure end and follow-up (Fig. 2). No device associated complications occurred. By 30 days, there was one non-cardiac death and one major bleeding. At follow-up, all but one patient had at least one grade reduction in NYHA class (10/10 vs 19/20, p=1.000). Kansas City Cardiomyopathy Questionnaire score and 6-minute walk distance similarly improved (Δ20.7±14.9 vs 15.5±7.9 points, p=0.227; Δ80.5±60.1 vs 46.6±30.6 meters, p=0.121). A statistical in-group difference was also noticed in renal function improvement by follow-up [glomerular filtration rate (GFR) TTE group 56.8±18.7 vs 64.8±12.5 ml/m2/1.73 m2, p=0.028; TOE group 50.7±19.9 vs 62.2±25.9, p=0.001]. Conclusion TTE guidance of TTVR is feasible in selected patients with excellent acoustic window and could offer an alternative in case of high anesthetic risk. Similar procedural success and clinical outcomes, as with TOE guidance, can be achieved. Funding Acknowledgement Type of funding sources: None.

The clinical and biochemical effects of atrial fibrillation on heart failure with reduced ejection fraction; a sub-saharan African perspective

Abstract Background Sub Saharan Africa (SSA) has seen one of the sharpest increases in cardiovascular disease-related mortality. This increase is evidenced by a growing burden of heart failure and atrial fibrillation (AF) risk factors. Atrial fibrillation is a common comorbidity of heart failure with reduced ejection fraction (HFrEF) which predisposes to an increased risk of morbidity and mortality. Studies done in high income countries (HIC) suggest that there may be an essential role for ethnic differences. However, in the absence of accurate epidemiological data in Sub-Saharan Africa, this cannot be proven. To date, there has never been a prospective systematic description of patients with HFrEF/AF and HFrEF/sinus rhythm (SR). Aim Our study aimed to describe the clinical and biochemical profile of patients with HFrEF/AF and HFrEF/SR in a Sub-Saharan African cohort. Methods The study was conducted inthe division of our Academic Hospital in South Africa. We enrolled 141 patients, consecutively, with HFrEF. Baseline clinical characteristics and exploratory biomarkers were recorded. All participants underwent comprehensive echocardiography. Novel left atrial strain was measured using 2D-speckle tracking echocardiography. These values were compared between patients in SR and in AF. Results The prevalence of AF was 21.38%. Hypertensive heart disease was the leading cause of HFrEF (36%). HFrEF/AF patients were significantly older (66.7±11.9) than those in SR (53.7±14.4) (p=0.000) with significantly different racial proportions (p=0.001). Coronary artery disease was prevalent in patients with HFrEF/AF. Patients with HFrEF/AF had significantly lower Kansas City Cardiomyopathy Questionnaire scores (29.83±15.27) compared to those in SR (44.26±16.30) (p=0.000) as well as worsening functional class (NYHA III–IV; 64.3% vs 22.7%, p=0.000). Measured levels of sST2 were greater in HFrEF/AF patients 40.45ng/mL (17.6–68.6) vs 20.8 (7.9–44.0) in HFrEF/SR (p=0.031). Patients with HFrEF/AF had a significantly greater left atrial volume (ml) (83.9 [64–99.9]) than those with HFrEF/SR (61.53±25.46) (p=0.038). Left atrial strain reservoir function (%) was significantly lower in patients with HFrEF/AF (29.00±13.60) compared to those with HFrEF/SR (41.56±15.46) (p=0.0004) Conclusion Our findings demonstrate that patients with HFrEF/AF are older than those in SR but much younger compared to patients in HICs. Hypertensive heart disease is a major cause of HFrEF in South Africa. We demonstrate that patients with HFrEF/AF are clinically worse off than those with HFrEF/SR. Atrial fibrillation is a marker of fibrosis and disease severity in HFrEF. Patients with HFrEF/AF had elevated sST2 levels a more deformed left atrium morphologically and poor tissue doppler function. On strain imaging, HFrEF/AF patients had poor left atrial reservoir function. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The South African Medical Research Council

1-Year Outcomes of Cardioband Tricuspid Valve Reconstruction System Early Feasibility Study.

Tricuspid regurgitation (TR) is prevalent and undertreated, with mortality and morbidity increasing with TR severity. Given poor outcomes with medical therapy and high in-hospital mortality for isolated tricuspid valve surgery, emerging transcatheter repair devices offer a promising alternative. The Edwards Cardioband Tricuspid Valve Reconstruction System Early Feasibility study (NCT03382457) evaluates the treatment of functional TR via annular reduction with the Cardioband Tricuspid Valve Reconstruction System (Edwards Lifesciences). Patients with≥ moderate functional TR were eligible for this prospective, single-arm multicenter study. At 1year, patients were evaluated for echocardiographic parameters, clinical and quality-of-life measures, and major adverse events. The 37 patients enrolled had a mean age of 78 years; 76% were female; and they had≥ severe functional (97.3%) or mixed (2.7%) TR, atrial flutter/fibrillation (97%), and New York Heart Association functional class III/IV (65%). At 1 year, 73.0% achieved≤ moderate TR (P< 0.0001), and 73.1% had≥2 grade reductions. Echocardiography showedsignificant reductions in the tricuspid annulus diameter (P< 0.0001), mean vena contracta (P< 0.0001), proximal isovelocity surface area effective regurgitant orifice area (P< 0.0001), right ventricular end-diastolic diameter (P< 0.0001), and inferior vena contracta (P = 0.0006). New York Heart Association functional class improved significantly (P< 0.0001), with 92.3% achieving class I/II, and Kansas City Cardiomyopathy Questionnaire scores improved by 19.0 points (P< 0.0001). One-year cardiovascular mortality was 8.1%, reinterventions were necessary in 5.4%, major access site complications occurred in 8.1%, and severe bleeding was noted in 35.1% of patients. Kaplan-Meier estimates of survival and freedom from heart failure rehospitalization were 85.9% and 88.7%, respectively. One-year experience using the Cardioband system for tricuspid valve repair shows high survival and low rehospitalization rates with durable outcomes in TR reduction and echocardiographic, clinical, and quality-of-life outcomes.

Effects of Empagliflozin in Women and Men With Heart Failure and Preserved Ejection Fraction.

Background:Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction).Methods:The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%–49%, 50%–59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed.Results:Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; Pinteraction=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; Pinteraction=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score.Conclusions:Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.

Long-Term Efficacy and Safety of ARRY-371797 (PF-07265803) in Patients With Lamin A/C–Related Dilated Cardiomyopathy

Dilated cardiomyopathy associated with lamin A/C (LMNA) gene variants (LMNA-related dilated cardiomyopathy [DCM]) is a life-threatening condition with a high unmet need, accounting for approximately 6% of idiopathic DCM cases. Currently, no disease-specific treatments target the underlying disease mechanism. ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study. This long-term extension study examined the safety and efficacy of ARRY-371797 in patients from the phase 2 study. 6MWT, N-terminal pro-B-type natriuretic peptide concentration, and 12-item Kansas City Cardiomyopathy Questionnaire score were assessed at weeks 48, 72, 96, 120, and 144 from phase 2 study baseline. Eight patients enrolled (mean [SD] age, 51 [10] years, 4 male). Mean 6MWT increased by >30 m (>10%) from phase 2 study baseline up to week 120. The decrease in N-terminal pro-B-type natriuretic peptide observed in the phase 2 study was maintained throughout the present study. Twelve-item Kansas City Cardiomyopathy Questionnaire Physical Limitation increased from baseline at all visits except week 96 (range: -0.8 [week 96] to 13.8 [week 120]); results for other domains were variable. Treatment was generally well tolerated; 2 patients discontinued because of causes not considered treatment-related. There were no deaths. ARRY-371797 was generally well tolerated over median (range) 155.7 (61 to 327)-week exposure; evidence suggested preserved exercise capacity over the study period. The ongoing, pivotal, phase 3, randomized, placebo-controlled study REALM-DCM investigates the efficacy and safety of ARRY-371797 (PF-07265803) in LMNA-related DCM. (ClinicalTrials.gov Identifier: NCT02351856).

Clinical Outcomes With Transcatheter Edge-to-Edge Repair in Atrial Functional MR From the EXPAND Study

BackgroundAlthough transcatheter edge-to-edge repair (TEER) has been shown to improve clinical outcomes and improve quality of life in patients with symptomatic secondary mitral regurgitation (SMR) and left ventricular dysfunction, its effect in patients with atrial SMR (aSMR) has not been well described. ObjectivesThe aim of this study was to assess the safety, echocardiographic outcomes, and clinical effectiveness of TEER for aSMR. MethodsPatients with aSMR in the prospective, observational, multicenter EXPAND (A Contemporary, Prospective, Multi-Center Study Evaluating Real-World Experience of Performance and Safety for the Next Generation of MitraClip Devices) study were identified by an echocardiography core laboratory. Follow-up occurred at discharge, 30 days, and 1 year. Key endpoints included mitral regurgitation (MR) severity, functional class, heart failure hospitalizations, mortality, and 30-day major adverse events. ResultsAmong 1,041 patients enrolled in EXPAND, 835 patients had evaluable echocardiograms at baseline. Of these, 53 patients had aSMR and 360 had ventricular SMR (vSMR). In the aSMR cohort, TEER resulted in a significant reduction in MR through 1 year (MR grade ≤2 in 100.0%), significantly increased 1-year Kansas City Cardiomyopathy Questionnaire score (+26.6 ± 30.5 points; P < 0.0001), and improved functional class from baseline, similar to the effects among patients with vSMR (MR grade ≤2 in 99.5% at 1 year, 1-year increase in Kansas City Cardiomyopathy Questionnaire score 21.23 ± 24.92 points). Major adverse events at 30 days and leaflet adverse events at 1 year were infrequent in both groups. ConclusionsIn a prospective, real-world, global registry, TEER for aSMR was associated with significant MR reduction and improvement in quality of life and functional class, similar to patients with vSMR. This suggests that TEER may provide clinical benefit in patients with atrial fibrillation with SMR in the setting of heart failure with preserved ejection fraction. (The MitraClip® EXPAND Study of the Next Generation of MitraClip® Devices; NCT03502811)

Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure: A Prespecified Analysis of the DELIVER Trial.

Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death. Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI ≤0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI ≥0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P<0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; Pinteraction=0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class. In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty. URL: https://www. gov; Unique identifier: NCT03619213.

Heart failure-type symptom scores in chronic kidney disease: The importance of body mass index.

This analysis sought to determine factors (including adiposity-related factors) most associated with HF-type symptoms (fatigue, shortness of breath, and edema) in adults with chronic kidney disease (CKD). Symptom burden impairs quality of life in CKD, especially symptoms that overlap with HF. These symptoms are common regardless of clinical HF diagnosis, and may be affected by subtle cardiac dysfunction, kidney dysfunction, and other factors. We used machine learning to investigate cross-sectional relationships of clinical variables with symptom scores in a CKD cohort. Participants in the Chronic Renal Insufficiency Cohort (CRIC) with a baseline modified Kansas City Cardiomyopathy Questionnaire (KCCQ) score were included, regardless of prior HF diagnosis. The primary outcome was Overall Summary Score as a continuous measure. Predictors were 99 clinical variables representing demographic, cardiac, kidney and other health dimensions. A correlation filter was applied. Random forest regression models were fitted. Variable importance scores and adjusted predicted outcomes are presented. The cohort included 3426 individuals, 10.3% with prior HF diagnosis. BMI was the most important factor, with BMI 24.3 kg/m2 associated with the least symptoms. Symptoms worsened with higher or lower BMIs, with a potentially clinically relevant 5 point score decline at 35.7 kg/m2 and a 1-point decline at the threshold for low BMI, 18.5 kg/m2. The most important cardiac and kidney factors were heart rate and eGFR, the 4th and 5th most important variables, respectively. Results were similar for secondary analyses. In a CKD cohort, BMI was the most important feature for explaining HF-type symptoms regardless of clinical HF diagnosis, identifying an important focus for symptom directed investigations.

Sustained-Release Ivabradine Hemisulfate in Patients With Systolic Heart Failure

BackgroundIvabradine has potent actions in reducing heart rate and improving clinical outcomes of chronic heart failure with reduced ejection fraction (HFrEF). At present, only the short-acting formulation of ivabradine is available that needs to be administered twice daily. ObjectivesThis study sought to evaluate the role of ivabradine hemisulfate sustained release (SR), a novel long-acting formulation of ivabradine dosed once daily, in stable patients with HFrEF. MethodsPatients with stabilized HFrEF in New York Heart Association functional class II-IV were enrolled and randomized to receive placebo or ivabradine SR in addition to standard medications. The primary endpoint was the change of left ventricular (LV) end-systolic volume index from baseline to week 32. ResultsWe randomly assigned 181 patients to placebo and 179 patients to ivabradine SR. After 32 weeks, a significant improvement of LV end-systolic volume index from baseline was observed in both arms with a greater effect in the ivabradine SR arm. Ivabradine SR therapy also exhibited superiority in improving LV end-diastolic volume index, LV ejection fraction, resting heart rate, the Kansas City Cardiomyopathy Questionnaire score, and hospital admission for heart failure worsening and cardiovascular disease in comparison to placebo. Overall adverse events showed no difference between the treatment arms. There were fewer occurrences of worsening heart failure in the ivabradine SR arm. ConclusionsThe present study demonstrates that ivabradine SR once daily in addition to optimum standard therapy improved heart function in patients with HFrEF. (Clinical Trial of Systolic Heart Failure Treatment of IvabRadine Hemisulfate Sustained-release Tablets [FIRST]; NCT02188082)

Impact of empagliflozin on peak oxygen uptake in HFmrEF patients: a randomized controlled trial

Objective: To evaluate the impact of empagliflozin on peak oxygen uptake (VO2peak) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods: In this randomized controlled trial, consecutive HFmrEF patients admitted to the Department of Cardiology of China-Japan Friendship Hospital from September 2019 to October 2020 were screened, and randomly assigned to empagliflozin group (EG) or conventional group (CG) using a random number table. The enrolled patients were treated according to the guidelines, and patients in the empagliflozin group received additional empagliflozin (10 mg, once a day, orally) on top of the conventional treatment. The primary end points were VO2peak at 6 months after treatment, and the secondary end points included other parameters of cardiopulmonary exercise test (CPET), 6-minute walking distance, N-terminal B-type pro-natriuretic peptide (NT-proBNP) level, and Kansas City Cardiomyopathy Questionnaire (KCCQ) score. Results: A total of 112 patients were included (mean age 69 (57, 78) years, 84 male (75.0%)). There were 55 cases in CG group and 57 cases in EG group. There were no significant differences in baseline data including age, sex, body mass index, left ventricular ejection fraction, systolic blood pressure, heart rate, estimated glomerular filtration rate, glycosylated hemoglobin, hemoglobin, NT-proBNP, daily dose of tolasemi, combined medication, CPET parameters, the proportion of New York Heart Association heart function Ⅲ/Ⅳ, history of coronary heart disease, history of hypertension, history of diabetes (all P>0.05). At 6 months after treatment, VO2peak was significantly higher in EG group than in CG group(P=0.023). VE/VCO2 slope was significantly lower in EG group than in CG group(P=0.034). Oxygen uptake efficiency slope was significantly higher in EG group than in CG group(P=0.038). The level of NT-proBNP was significantly lower in EG group than in CG group(P=0.020). Six-minute walking distance was significantly higher in EG group than in CG group(P=0.037). KCCQ score was significantly higher in EG group than in CG group(P=0.048). Exercise oscillatory ventilation decreased in both groups (1 case in each group, P>0.05). Conclusion: Empagliflozin can significantly improve VO2peak in patients with HFmrEF.

Efficacy of three novel drugs in the treatment of heart failure: A network meta-analysis.

Background:Angiotensin receptor neprilysin inhibitors (ARNI), sodium-glucose cotransporter 2 inhibitors (SGLT2i), soluble guanylate cyclase stimulators (sGCs), and the traditional golden triangle standard-of-care (SOC) are effective drugs for heart failure. We aimed to assess the efficacy of 4 interventions in these patients.Methods:PubMed, The Cochrane Library, Embase, and Web of Science databases were electronically searched to collect randomized controlled trials of 3 novel drugs in the treatment of heart failure from inception to September 1st, 2021. Two reviewers independently screened literature, extracted data, and assessed the risk bias of included studies. Stata 16.0 software was used for network meta-analysis.Results:A total of 17 randomized controlled trial involving 38,088 patients were included. The results of network meta-analysis: in terms of heart failure rehospitalization rate, 3 novel drugs lower than SOC [ARNI (OR = 0.77, 95% CI: 0.71–0.83), SGLT2i (OR = 0.70, 95% CI: 0.63–0.77), sGCs (OR = 0.88, 95% CI: 0.78–0.99)], and SGLT2i was also lower than sGCs (OR = 0.79, 95% CI: 0.68–0.93). In terms of all-cause mortality, ARNI was lower than SOC (OR = 0.81, 95% CI: 0.66–0.99). In terms of cardiovascular mortality, ARNI and SGLT2i was lower than SOC (ARNI [OR = 0.80, 95% CI: 0.70–0.92], SGLT2i [OR = 0.87, 95% CI: 0.76–0.99]). In terms of rates of cardiovascular death or heart failure rehospitalization, 3 novel drugs lower than SOC (ARNI [OR = 0.76, 95% CI: 0.71–0.82], SGLT2i [OR = 0.76, 95% CI: 0.70–0.82], sGCs [OR = 0.87, 95% CI: 0.78–0.97]). In terms of Kansas city cardiomyopathy questionnaire score, ARNI and SGLT2i was superior to SOC (ARNI [MD = 1.43, 95% CI: 0.43–2.42], SGLT2i [MD = 1.88, 95% CI: 1.12–2.65]). In terms of N-terminal pro-B-type natriuretic peptide outcome indexes, SGLT2i was superior to SOC (MD = −134.63, 95% CI: −237.70 to −31.56). The results of Surface under the cumulative ranking sequencing: in terms of heart failure rehospitalization rate and rates of cardiovascular death or heart failure rehospitalization, the ranking was SGLT2i>ARNI>sGCs>SOC. in terms of all-cause mortality and cardiovascular mortality, the ranking was ARN>SGLT2i>sGCs>SOC. in terms of Kansas city cardiomyopathy questionnaire score and N-terminal pro-B-type natriuretic peptide outcome indexes, the ranking was SGLT2i>ARN>SOC.Conclusions:The available evidence suggests that all 3 novel heart failure drugs can improve the prognosis of heart failure. ARNI may be the most effective in reducing mortality, SGLT2i may be the most effective in improving quality of life, while sGCs may be inferior to ARNI and SGLT2i.

The development and initial validation of the PROMIS®+HF-27 and PROMIS+HF-10 profiles.

Heart failure (HF) is a common and morbid condition impacting multiple health domains. We previously reported the development of the PROMIS®-Plus-HF (PROMIS+HF) profile measure, including universal and HF-specific items. To facilitate use, we developed shorter, PROMIS+HF profiles intended for research and clinical use. Candidate items were selected based on psychometric properties and symptom range coverage. HF clinicians (n=43) rated item importance and clinical actionability. Based on these results, we developed the PROMIS+HF-27 and PROMIS+HF-10 profiles with summary scores (0-100) for overall, physical, mental, and social health. In a cross-sectional sample (n=600), we measured internal consistency reliability (Cronbach's alpha and Spearman-Brown), test-retest reliability (intraclass coefficient; n=100), known-groups validity via New York Heart Association (NYHA) class, and convergent validity with Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. In a longitudinal sample (n=75), we evaluated responsiveness of baseline/follow-up scores by calculating mean differences and Cohen's d and comparing with paired t-tests. Internal consistency was good to excellent (α 0.82-0.94) for all PROMIS+HF-27 scores and acceptable to good (α/Spearman-Brown 0.60-0.85) for PROMIS+HF-10 scores. Test-retest intraclass coefficients were acceptable to excellent (0.75-0.97). Both profiles demonstrated known-groups validity for the overall and physical health summary scores based on NYHA class, and convergent validity for nearly all scores compared with KCCQ scores. In the longitudinal sample, we demonstrated responsiveness for PROMIS+HF-27 and PROMIS+HF-10 overall and physical summary scores. For the PROMIS+HF overall summary scores, a group-based increase of 7.6-8.3 points represented a small to medium change (Cohen's d=0.40-0.42). For the PROMIS+HF physical summary scores, a group-based increase of 5.0-5.9 points represented a small to medium change (Cohen's d=0.29-0.35). The PROMIS+HF-27 and PROMIS+HF-10 profiles demonstrated good psychometric characteristics with evidence of responsiveness for overall and physical health. These new measures can facilitate patient-centred research and clinical care, such as improving care quality through symptom monitoring, facilitating shared decision-making, evaluating quality of care, assessing new interventions, and monitoring during the initiation and titration of guideline-directed medical therapy.

Impact of Non-cardiac Comorbidities on Long-Term Clinical Outcomes and Health Status After Acute Heart Failure in China.

BackgroundIndividual non-cardiac comorbidities are prevalent in HF; however, few studies reported how the aggregate burden of non-cardiac comorbidities affects long-term outcomes, and it is unknown whether this burden is associated with changes in health status.AimsTo assess the association of the overall burden of non-cardiac comorbidities with clinical outcomes and quality of life (QoL) in patients hospitalized for heart failure (HF).MethodsWe prospectively enrolled patients hospitalized for HF from 52 hospitals in China. Eight key non-cardiac comorbidities [diabetes, chronic renal disease, chronic obstructive pulmonary disease (COPD), anemia, stroke, cancer, peripheral arterial disease (PAD), and liver cirrhosis] were included, and patients were categorized into four groups: none, one, two, and three or more comorbidities. We fitted Cox proportional hazards models to assess the burden of comorbidities on 1-year death and rehospitalization.ResultsOf the 4,866 patients, 25.3% had no non-cardiac comorbidity, 32.2% had one, 22.9% had two, and 19.6% had three or more in China. Compared with those without non-cardiac comorbidities, patients with three or more comorbidities had higher risks of 1-year all-cause death [heart rate, HR 1.89; 95% confidence interval (CI) 1.48–2.39] and all-rehospitalization (HR 1.35; 95%CI 1.15–1.58) after adjustment. Although all patients with HF experienced a longitudinal improvement in QoL in the 180 days after discharge, those with three or more non-cardiac comorbidities had an unadjusted 11.4 (95%CI −13.4 to −9.4) lower Kansas City Cardiomyopathy Questionnaire (KCCQ) scores than patients without comorbidities. This difference decreased to −6.4 (95%CI −8.6 to −4.2) after adjustment for covariates.ConclusionAmong patients hospitalized with HF in this study, a higher burden of non-cardiac comorbidities was significantly associated with worse health-related QoL (HRQoL), increased risks of death, and rehospitalization post-discharge. The findings highlight the need to address the management of comorbidities effectively in standardized HF care.