Reduced functional capacity is associated with the proportion of impaired myocardial deformation assessed in heart failure patients by CMR.

Aims: Heart failure (HF) does not only reduce the life expectancy in patients, but their life is also often limited by HF symptoms leading to a reduced quality of life (QoL) and a diminished exercise capacity. Novel parameters in cardiac imaging, including both global and regional myocardial strain imaging, promise to contribute to better patient characterization and ultimately to better patient management. However, many of these methods are not part of clinical routine yet, their associations with clinical parameters have been poorly studied. An imaging parameters that also indicate the clinical symptom burden of HF patients would make cardiac imaging more robust toward incomplete clinical information and support the clinical decision process. Methods and results: This prospective study conducted at two centers in Germany between 2017 and 2018 enrolled stable outpatient subjects with HF [n = 56, including HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF)] and a control cohort (n = 19). Parameters assessed included measures for external myocardial function, for example, cardiac index and myocardial deformation measurements by cardiovascular magnetic resonance imaging, left ventricular global longitudinal strain (GLS), the global circumferential strain (GCS), and the regional distribution of segment deformation within the LV myocardium, as well as basic phenotypical characteristics including the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the 6-minute walk test (6MWT). If less than 80% of the LV segments are preserved in their deformation capacity the functional capacity by 6MWT (6 minutes walking distance: MyoHealth ≥ 80%: 579.8 ± 177.6 m; MyoHealth 60-<80%: 401.3 ± 121.7 m; MyoHealth 40-<60%: 456.4 ± 68.9 m; MyoHealth < 40%: 397.6 ± 125.9 m, overall p-value: 0.03) as well as the symptom burden are significantly impaired (NYHA class: MyoHealth ≥ 80%: 0.6 ± 1.1 m; MyoHealth 60-<80%: 1.7 ± 1.2 m; MyoHealth 40-<60%: 1.8 ± 0.7 m; MyoHealth < 40%: 2.4 ± 0.5 m; overall p-value < 0.01). Differences were also observed in the perceived exertion assessed by on the Borg scale (MyoHealth ≥ 80%: 8.2 ± 2.3 m; MyoHealth 60-<80%: 10.4 ± 3.2 m; MyoHealth 40-<60%: 9.8 ± 2.1 m; MyoHealth < 40%: 11.0 ± 2.9 m; overall p-value: 0.20) as well as quality of life measures (MLHFQ; MyoHealth ≥ 80%: 7.5 ± 12.4 m; MyoHealth 60-<80%: 23.4 ± 23.4 m; MyoHealth 40-<60%: 20.5 ± 21.2 m; MyoHealth < 40%: 27.4 ± 24.4 m; overall p-value: 0.15)-while these differences were not significant. Conclusion: The share of LV segments with preserved myocardial contraction promises to discriminate between symptomatic and asymptomatic subjects based on the imaging findings, even when the LV ejection fraction is preserved. This finding is promising to make imaging studies more robust toward incomplete clinical information.

Myocardial deformation assessed among heart failure entities by cardiovascular magnetic resonance imaging.

AIMS: Although heart failure (HF) is a leading cause for hospitalization and mortality, normalized and comparable non-invasive assessment of haemodynamics and myocardial action remains limited. Moreover, myocardial deformation has not been compared between the guideline-defined HF entities. The distribution of affected and impaired segments within the contracting left ventricular (LV) myocardium have also not been compared. Therefore, we assessed myocardial function impairment by strain in patients with HF and control subjects by magnetic resonance imaging after clinically phenotyping these patients. METHODS AND RESULTS: This prospective study conducted at two centres in Germany between 2017 and 2018 enrolled stable outpatient subjects with HF [n = 56, including HF with reduced ejection fraction (HFrEF), HF with mid-range ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF)] and a control cohort (n = 12). Parameters assessed included measures for external myocardial function, for example, cardiac index and myocardial deformation measurements by cardiovascular magnetic resonance imaging, left ventricular global longitudinal strain (GLS), the global circumferential strain (GCS) and the regional distribution of segment deformation within the LV myocardium, as well as basic phenotypical characteristics. Comparison of the cardiac indices at rest showed no differences neither between the HF groups nor between the control group and HF patients (one-way ANOVA P = 0.70). The analysis of the strain data revealed differences between all groups in both LV GLS (One-way ANOVA: P < 0.01. Controls vs. HFpEF: -20.48 ± 1.62 vs. -19.27 ± 1.25. HFpEF vs. HFmrEF: -19.27 ± 1.25 vs. -15.72 ± 2.76. HFmrEF vs. HFrEF: -15.72 ± 2.76 vs. -11.51 ± 3.97.) and LV GCS (One-way ANOVA: P < 0.01. Controls vs. HFpEF: -19.74 ± 2.18 vs. -17.47 ± 2.10. HFpEF vs. HFmrEF: -17.47 ± 2.10 vs. -12.78 ± 3.47. HFrEF: -11.41 ± 3.27). Comparing the segment deformation distribution patterns highlighted the discriminating effect between the groups was much more prominent between the groups (one-way ANOVA P < 0.01) when compared by a score combining regional effects and a global view on the LV. Further analyses of the patterns among the segments affected showed that while the LVEF is preserved in HFpEF, the segments impaired in their contractility are located in the ventricular septum. The worse the LVEF is, the more segments are affected, but the septum remains an outstanding location with the most severe contractility impairment throughout the HF entities. CONCLUSIONS: While cardiac index at rest did not differ significantly between controls and stable HF patients suffering from HFrEF, HFmrEF, or HFpEF, the groups did differ significantly in LV GLS and LV GCS values. Regional strain analysis revealed that the LV septum is the location affected most, with reduced values already visible in HFpEF and further reductions in HFmrEF and HFrEF.

Cardio-microcurrent device for chronic heart failure: first-in-human clinical study.

AIMS: Most devices for treating ambulatory Class II and III heart failure are linked to electrical pulses. However, a steady electric potential gradient is also necessary for appropriate myocardial performance and may be disturbed by structural heart diseases. We investigated whether chronic application of electrical microcurrent to the heart is feasible and safe and improves cardiac performance. The results of this study should provide guidance for the design of a two-arm, randomized, controlled Phase II trial. METHODS AND RESULTS: This single-arm, non-randomized pilot study involved 10 patients (9 men; mean age, 62 ± 12 years) at two sites with 6 month follow-up. All patients had New York Heart Association (NYHA) Class III heart failure and non-ischaemic dilated cardiomyopathy, with left ventricular ejection fraction (LVEF) <35%. A device was surgically placed to deliver a constant microcurrent to the heart. The following tests were performed at baseline, at hospital discharge, and at six time points during follow-up: determination of LVEF and left ventricular end-diastolic/end-systolic diameter by echocardiography; the 6 min walk test; and assessment of NYHA classification and quality of life (36-Item Short-Form Health Survey questionnaire). Microcurrent application was feasible and safe; no device-related or treatment-related adverse events occurred. During follow-up, rapid and significant signal of efficacy (P < 0.005) was present with improvements in LVEF, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and distance walked. For eight patients, NYHA classification improved from Class III to Class I (for seven, as early as 14 days post-operatively); for one, to Class II; and for one, to Class II/III. 36-Item Short-Form Health Survey questionnaire scores also improved highly significantly. CONCLUSIONS: Chronic application of microcurrent to the heart is feasible and safe and leads to a rapid and lasting improvement in heart function and a near normalization of heart size within days. The NYHA classification and quality of life improve just as rapidly.

Effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute myocardial infarction-Results of the Chymase Inhibitor in Adverse Remodeling after Myocardial Infarction (CHIARA MIA) 2 trial.

BACKGROUND: Adverse cardiac remodeling is a major risk factor for the development of post myocardial infarction (MI) heart failure (HF). This study investigates the effects of the chymase inhibitor fulacimstat on adverse cardiac remodeling after acute ST-segment-elevation myocardial infarction (STEMI). METHODS: In this double-blind, randomized, placebo-controlled trial patients with first STEMI were eligible. To preferentially enrich patients at high risk of adverse remodeling, main inclusion criteria were a left-ventricular ejection fraction (LVEF) ≤45% and an infarct size >10% on day 5 to 9 post MI as measured by cardiac MRI. Patients were then randomized to 6 months treatment with either 25 mg fulacimstat (n = 54) or placebo (n = 53) twice daily on top of standard of care starting day 6 to 12 post MI. The changes in LVEF, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume index (LVESVI) from baseline to 6 months were analyzed by a central blinded cardiac MRI core laboratory. RESULTS: Fulacimstat was safe and well tolerated and achieved mean total trough concentrations that were approximately tenfold higher than those predicted to be required for minimal therapeutic activity. Comparable changes in LVEF (fulacimstat: 3.5% ±â€¯5.4%, placebo: 4.0% ±â€¯5.0%, P = .69), LVEDVI (fulacimstat: 7.3 ±â€¯13.3 mL/m2, placebo: 5.1 ±â€¯18.9 mL/m2, P = .54), and LVESVI (fulacimstat: 2.3 ±â€¯11.2 mL/m2, placebo: 0.6 ±â€¯14.8 mL/m2, P = .56) were observed in both treatment arms. CONCLUSION: Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on cardiac remodeling.

Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP and GDF-15, of Heart Failure therapies (STRONG-HF): rationale and design for a multicentre, randomized, parallel-group study.

AIMS: Patients admitted for acute heart failure (HF) are at high risk of readmission and death, especially in the 90 days following discharge. We aimed to assess the safety and efficacy of early optimization of oral HF therapy with beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNi), and mineralocorticoid receptor antagonists (MRA) on 90-day clinical outcomes in patients admitted for acute HF. METHODS: In a multicentre, randomized, open-label, parallel-group study, a total of 900 patients will be randomized in a 1:1 ratio to either 'usual care' or 'high-intensity care'. Patients enrolled in the usual care arm will be discharged and managed according to usual clinical practice at the site. In the high-intensity care arm, doses of oral HF medications - including a BB, ACEi or ARB, and MRA - will be up-titrated to 50% of recommended doses before discharge and to 100% of recommended doses within 2 weeks of discharge. Up-titration will be delayed if the patients develop worsening symptoms and signs of congestion, hyperkalaemia, hypotension, bradycardia, worsening of renal function or significant increase in N-terminal pro-B-type natriuretic peptide between visits. The primary endpoint is 90-day all-cause mortality or HF readmission. CONCLUSIONS: STRONG-HF is the first study to assess whether rapid up-titration of evidence-based guideline-recommended therapies with close follow-up in a large cohort of patients discharged from an acute HF admission is safe and can affect adverse outcomes during the first 90 days after discharge. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03412201.

Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial.

BACKGROUND: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. METHODS AND RESULTS: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), ß-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. CONCLUSIONS: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Ghrelin and hormonal markers under exercise training in patients with heart failure with preserved ejection fraction: results from the Ex-DHF pilot study.

BACKGROUND: Over 50% of patients with symptomatic heart failure (HF) experience HF with preserved ejection fraction (HFpEF). Exercise training (ET) is effective in improving cardiorespiratory fitness and dimensions of quality of life in patients with HFpEF. A systemic pro-inflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations has been proposed in HFpEF. ET modifies myocardial structure and has been related to inflammatory state. We investigated Ghrelin, related adipokines, markers of inflammation, and neuro-hormonal activation in patients undergoing a structured ET vs. usual care are with HFpEF. METHODS AND RESULTS: Ex-DHF-P was a prospective, controlled, randomized multi-centre trial on structured and supervised ET in patients with HFpEF. We performed a post hoc analysis in 62 patients from Ex-DHF-P. Ghrelin, adiponectin, leptin, IL-1ß, IL-6, IL-10, tumour necrosis factor-alpha, MR-proANP, MR-proADM, CT-proET1, and CT-proAVP were assessed to seize the impact of ET on these markers in patients with HFpEF. Thirty-six (58%) patients were female, mean age was 64 years, and median ghrelin was 928 pg/mL (interquartile range 755-1156). When stratified for high versus low ghrelin, groups significantly differed at baseline in presence obesity, waist circumference, and adiponectin levels (P < 0.05, respectively). Overall, ghrelin levels rose significantly to 1013 pg/mL (interquartile range 813-1182) (P < 0.001). Analysis of covariance modelling for change in ghrelin identified ET (P = 0.013) and higher baseline adiponectin levels (P = 0.035) as influencing factors. CONCLUSIONS: Exercise training tended to increase ghrelin levels in Ex-DHF-P. This increase was especially pronounced in patients with higher baseline adiponectin levels. Future trials are needed to investigate the effect of ET on endogenous ghrelin levels in regard to interactions with cardiac structure and clinically meaningful surrogate parameters.

Estimating fat mass in heart failure patients.

INTRODUCTION: Body composition (BC) assessments in heart failure (HF) patients are mainly based on body weight, body mass index and waist-to-hip ratio. The present study compares BC assessments by basic anthropometry, dual energy X-ray absorptiometry (DXA), bioelectrical impedance spectroscopy (BIS), and air displacement plethysmography (ADP) for the estimation of fat (FM) and fat-free mass (FFM) in a HF population. MATERIAL AND METHODS: In this single-centre, observational pilot study we enrolled 52 patients with HF (33 HF with reduced ejection fraction (HFrEF), 19 HF with preserved ejection fraction (HFpEF); mean age was 67.7 ±9.9 years, 41 male) and 20 healthy controls. DXA was used as a reference standard for the measurement of FM and FFM. RESULTS: In the HF population, linear regression for DXA-FM and waist-to-hip ratio (r = -0.05, 95% CI: (-0.32)-0.23), body mass index (r = 0.47, 95% CI: 0.23-0.669), and body density (r = -0.87, 95% CI: (-0.93)-(-0.87)) was obtained. In HF, Lin's concordance correlation coefficient of DXA-FM (%) with ADP-FM (%) was 0.76 (95% CI: 0.64-0.85) and DXA-FFM [kg] with DXA-ADP [kg] was 0.93 (95% CI: 0.88-0.96). DXA-FM (%) for BIS-FM (%) was 0.69 (95% CI: 0.54-0.80) and 0.73 (95% CI: 0.60-0.82) for DXA-FFM [kg] and BIS-FFM [kg]. CONCLUSIONS: Body density is a useful surrogate for FM. ADP was found suitable for estimating FM (%) and FFM [kg] in HF patients. BIS showed acceptable results for the estimation of FM (%) in HFrEF and for FFM [kg] in HFpEF patients. We encourage selecting a suitable method for BC assessment according to the compartment of interest in the HF population.

Comparison of self-care behaviors of heart failure patients in 15 countries worldwide.

OBJECTIVE: Clinicians worldwide seek to educate and support heart failure patients to engage in self-care. We aimed to describe self-care behaviors of patients from 15 countries across three continents. METHODS: Data on self-care were pooled from 5964 heart failure patients from the United States, Europe, Australasia and South America. Data on self-care were collected with the Self-care of Heart Failure Index or the European Heart Failure Self-care Behavior Scale. RESULTS: In all the samples, most patients reported taking their medications as prescribed but exercise and weight monitoring were low. In 14 of the 22 samples, more than 50% of the patients reported low exercise levels. In 16 samples, less than half of the patients weighed themselves regularly, with large differences among the countries. Self-care with regard to receiving an annual flu shot and following a low sodium diet varied most across the countries. CONCLUSION: Self-care behaviors are sub-optimal in heart failure patients and need to be improved worldwide. PRACTICE IMPLICATIONS: Interventions that focus on specific self-care behaviors may be more effective than general educational programs. Changes in some health care systems and national policies are needed to support patients with heart failure to increase their self-care behavior.