Heart Failure With Reduced Ejection Fraction Patients Research Articles

Introduction of SGLT2 Inhibitors and Variations in Other Disease-Modifying Drugs in Heart Failure Patients: A Single-Centre Real-World Experience.

The sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as a crucial therapeutic option for patients with chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate, in a real-world population from a single centre, the feasibility of introducing SGLT2i and their interaction with other recommended drug classes. Consecutive patients affected by chronic heart failure (CHF) were evaluated beginning in January 2022. At the baseline clinical visit, both the patient's current medication and the prescribed treatments were recorded. Over a 6- to 12-month follow-up, changes in concomitant therapy were analysed. At baseline, among 350 patients evaluated, only 17 (5%) were already taking SGLT2i: 13 with HFrEF, five with mildly reduced (HFmrEF), preserved (HFpEF) or improved (HFimpEF) ejection fraction. After the baseline assessment, SGLT2i were prescribed to 224 (64%) of the patients, including 179 (84%) with HFrEF, 27 (42%) with HFmrEF/HFimpEF, and 18 (22%) with HFpEF/HFimpEF. After follow-up, SGLT2i therapy was well tolerated and was associated with a significant increase in sacubitril/valsartan prescriptions and a decrease in diuretic use. Finally, a significant improvement in functional status and left ventricular systolic function after SGLT2i therapy was observed. In this single-centre, real-world study, SGLT2i were primarily prescribed to HFrEF patients who were already on other recommended drug classes for their treatment. Additionally, there was a noticeable enhancement in the prescribed therapy during a short-term follow-up. These findings further bolster the inclusion of this therapeutic approach in regular clinical practice.

Prognostic implications of left ventricular ejection fraction trajectory changes in heart failure.

The latest guidelines recommended to assess the trajectory of left ventricular ejection fraction (LVEF) in patients with heart failure (HF). However, there is limited data on the trajectory of LVEF in real-world settings. In this study, we investigated the frequency and prognostic implications of changes in LVEF trajectory. Patients were divided into intensified LVEF, static LVEF, and worsening LVEF groups based on the transitions of HF types from baseline to follow-up. The intensified and worsening LVEF groups were further subdivided into mild (≤10% absolute changes of LVEF) and significant (>10% absolute changes of LVEF) increase or decrease groups according to the magnitude of change. The incidences and associations of changes in LVEF with patient outcomes were analyzed. Among the 2,429 patients in the study cohort, 38.3% of HF with reduced ejection fraction (HFrEF) and 37.6% of HF with mildly reduced ejection fraction (HFmrEF) showed an improvement in their LVEF. In contrast, a decline in LVEF was observed in 19.3% of HF patients with preserved ejection fraction (HFpEF) and 34.9% of those with HFmrEF. Cox regression analysis showed that the intensified LVEF group was associated with a lower risk of composite endpoints, while the worsening LVEF group yielded opposite findings. Subgroup analysis revealed that compared to those with mild changes in LVEF, baseline HFrEF patients with significant increase showed a lower risk of composite outcome, while baseline HFpEF patients were the opposite. The trajectories of LVEF changes are strongly correlated with outcomes in patients with HF who had prior history of HF admission. The most significant prognostic implications observed in patients with significant LVEF changes. Trajectory LVEF and type of HF changes are useful tools recommended for prognostication.

Clinical Inertia Among Outpatients With Heart Failure: Application of Treatment Nonintensification Taxonomy to EPIC-HF Trial

BackgroundThe contribution of clinical inertia to suboptimal guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF) remains unclear. ObjectivesThis study examined reasons for GDMT nonintensification and characterized clinical inertia. MethodsIn this secondary analysis of EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction), a randomized clinical trial evaluating a patient-activation tool on GDMT utilization, we performed a sequential, explanatory mixed-methods study. Reasons for nonintensification among 4 medication classes were assigned according to an expanded published taxonomy using structured chart reviews. Audio transcripts of clinic encounters were analyzed to further characterize nonintensification reasons. Integration occurred during the interpretation phase. ResultsAmong 292 HFrEF patients who completed a cardiology visit, 185 (63.4%) experienced no treatment intensification, of whom 90 (48.6%) had at least 1 opportunity for intensification of a medication class with no documented contraindication or barriers (ie, clinical inertia). Nonintensification reasons varied by medication class, and included heightened risk of adverse effects (range 18.2%-31.6%), patient nonadherence (range 0.8%-1.1%), patient preferences and beliefs (range 0.6%-0.9%), comanagement with other providers (range 4.6%-5.6%), prioritization of other issues (range 15.6%-31.8%), multiple categories (range 16.5%-22.7%), and clinical inertia (range 22.7%-31.6%). A qualitative analysis of 32 clinic audio recordings demonstrated common characteristics of clinical inertia: 1) clinician review of medication regimens without education or intensification discussions; 2) patient stability as justification for nonintensification; and 3) shorter encounters for nonintensification vs intensification. ConclusionsIn this comprehensive study exploring HFrEF prescribing, clinical inertia is a main contributor to nonintensification within an updated taxonomy classification for suboptimal GDMT prescribing. This approach should help target strategies overcoming GDMT underuse.

Safety and Efficacy of Nondihydropyridine Calcium Channel Blockers for Acute Rate Control in Atrial Fibrillation with Rapid Ventricular Response and Comorbid Heart Failure with Reduced Ejection Fraction.

The use of nondihydropyridine calcium channel blockers (NDCCBs) to achieve rate control in atrial fibrillation with the rapid ventricular rate (AF RVR) is not recommended in patients with comorbid heart failure with reduced ejection fraction (HFrEF) due to the concern for further blunting of contractility. However, these recommendations are extrapolated from data examining chronic NDCCB use in HFrEF patients, and comorbid AF was not analyzed. These recommendations also do not cite the hemodynamic effects or clinical outcomes of NDCCBs for acute rate control in HFrEF patients with AF RVR. It is our goal to open the discussion concerning the hemodynamic effects and safety profile of NDCCBs for acute rate control in this specific patient population. In the acute setting of AF RVR and HFrEF, there is a paucity of low-quality data on the safety and hemodynamic effects of NDCCBs, with mixed results. There has not been a clear signal toward adverse outcomes with NDCCBs, particularly for diltiazem. Data in this scenario is similarly limited for beta blockers, which provide the additional hemodynamic effect of the neurohormonal blockade, which provides a long-term mortality benefit to HFrEF patients. We support the cautious use of beta blockers as first-line therapy in clinical settings where an acute rate control strategy for AF RVR is warranted. We also support diltiazem as a reasonable second-line option, though the relative paucity of data calls for further research to validate this conclusion. Verapamil in this setting should be avoided until more data are available.

The Increasing Complexity of Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction and Challenges for Real-world Implementation

The latest guidelines for heart failure with reduced ejection fraction (HFrEF) recommend concurrent treatment with four drug classes to improve patient outcomes. While physicians likely have the skillsets needed to navigate the complexities of multiple drug interactions, HF nurse prescribers lack experience needed to implement the latest guideline-directed medical therapy (GDMT). As nurse-led HF services continue to expand, implementing GDMT is essential for gold-standard care. We describe and compare the abilities of physician-led and nurse-led HF clinics in implementing GDMT in HFrEF within the outpatient setting. A retrospective multi-centre cohort study was performed on the pharmacotherapy patterns of HFrEF patients attending either a physician-led or nurse-led HF clinic in 2021. Pharmacotherapy patterns of prescribing on the pillars of HFrEF therapy were collected: ACEi/ARB/ARNi, BB, MRA, SGLT2i. 164 and 231 HFrEF patients were reviewed in a physician-led and nurse-led group respectively. Compared to physicians, there were significantly lower rates of MRA (42.0% vs 62.8%, P < 0.001) and SGLT2i (7.8% vs 24.4%, P < 0.001) prescribed by nurses. Most patients seen by physicians were treated with three drug classes (45.7%) versus two drug classes (50.2%) when seen by nurses. Ongoing gaps in GDMT implementation are driven by the suboptimal MRA and SGLT2i use. Patients seen by nurses were treated with less drug classes and less likely to be treated with MRA and SGLT2i compared to physicians. These findings highlight the ongoing difficulties autonomous nurse prescribers face in HF prescribing and the need for further educational supports.

Short-term outcomes after sodium-glucose cotransporter-2 inhibitor initiation in a cohort of heart failure patients.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) decrease mortality and risk of hospitalization in patients with heart failure with reduced ejection fraction (HFrEF). SGLT2i have a natriuretic effect shortly after initiation, followed by a lasting osmotic diuretic effect. We sought to evaluate rates of acute kidney injury (AKI) and therapy discontinuation with SGLT2i initiation in a real-world cohort of HFrEF patients. We abstracted data on 200 patients with HFrEF initiated on a SGLT2i in the outpatient setting at the University of Michigan (between 1 July 2016 and 2 July 2022). Our co-primary endpoints were rate of AKI and discontinuation of SGLT2i. A total of 200 patients were included. The majority of patients were male (64%) with a mean left ventricular ejection fraction (LVEF) of 27%. One hundred and four (52%) patients had diabetes mellitus. Most patients exhibited New York Heart Association class II (51.5%) or III (33.5%) symptoms. The majority of patients (54%) were taking an angiotensin-receptor neprilysin inhibitor. The mean daily furosemide equivalent diuretic dose was 93.3mg. AKI occurred in 22 patients and 18 patients discontinued their SGLT2i. Yeast infection (n=6), hypotension (n=5), and AKI (n=4) were the most common reasons for discontinuation. Using receiver operating characteristic curve analysis, the strongest models for AKI were A1C [area underneath its curve (AUC)=75.8, empirical confidence interval (ECI) 66.5-83.5]; baseline serum creatinine (SCr) (AUC=72.0, ECI 65.7-78.7); LVEF (AUC=67.6, ECI 58.4-75.8); and furosemide equivalent diuretic dose (AUC=66.0, ECI 57.5-74.6). Similarly, the strongest positive models for SGLT2i discontinuation were A1C (AUC=81.1, ECI 74.8-87.2); baseline SCr (AUC=67.4, ECI 58.7-75.5); LVEF (AUC=68.7, ECI 58.9-76.5); and furosemide equivalent diuretic dose (AUC=67.2, ECI 58.2-76.0). A1C was the strongest model of AKI, and SGLT2i discontinuation in HFrEF patients started on SGLT2i. Glucosuria may be related to this effect. Patients with higher baseline SCr on higher doses of loop diuretics may be at greater risk of these outcomes. Future prospective studies will be needed to further evaluate these findings and other models of AKI and SGLT2i discontinuation to guide clinical use of SGLT2 inhibitors.

Abstract P2111: Characterizing Human Cardiac Fibroblast Responsiveness To Hemodynamic Unloading In Heart Failure With Reduced Ejection Fraction

Background: Myocardial interstitial fibrosis is a common pathology in cardiomyopathies leading to ventricular dilation and increased hemodynamic load that result in heart failure with reduced ejection fraction (HFrEF). Previous research has shown that HFrEF patients treated with a left ventricular assist device (LVAD) undergo hemodynamic unloading resulting in at least partial cardiomyocyte recovery. However, evidence supports that these patients do not experience a regression of fibrosis and demonstrate, in some cases, a worsening of fibrosis after LVAD treatment. Purpose: We hypothesize that human cardiac fibroblasts (HCFs) are constitutively activated in HFrEF myocardium but remain unresponsive to hemodynamic unloading with LVAD placement. Methods and Results: Forty human subjects with HFrEF undergoing LVAD implantation were enrolled to provide a portion of myocardium routinely removed during LVAD placement. In addition, 7 biopsies previously collected from transplanted hearts with extended LVAD treatment were also evaluated (LVEX). Quantification of PSR stained sections revealed a significant increase in collagen content in the HFrEF tissue (Collagen volume fraction % (CVF) = 2.8±0.2) in comparison to control tissues (CVF = 0.9±0.2) that remained elevated in LVEX hearts (CVF = 3.1±0.3). HCFs derived from biopsies received at LVAD placement were isolated and grown to confluence. HCFs from HFrEF patients and control HCFs from healthy donors were then plated on substrates with mechanical stiffnesses reflective of either normal myocardium (2kPa) or failing myocardium (8kPa). Cells were collected at 4- and 7-day timepoints and levels of collagen I (Col I) and alpha-smooth muscle actin (α-SMA) were quantified through western blot analysis with β-actin as a loading control. Whereas control HCFs were responsive to changes in substrate stiffness producing more Col I and α-SMA on 8kPa versus 2kPa, HCFs from HFrEF patients were unresponsive to changes in stiffness exhibiting no significant difference in production on 2 vs. 8kPa. Conclusion: These data suggest that HCFs isolated from the failing myocardium do not respond to changes in mechanical load and hence, might contribute to persistent increases in fibrosis in failing and unloaded hearts.

Association of insulin use with LV remodeling and clinical outcomes in diabetic patients with heart failure and reduced ejection fraction: assessed by cardiac MRI

BackgroundInsulin is commonly used in type 2 diabetes mellitus (T2DM) to achieve glycemic control. However, recent evidence showed that insulin use is associated with poor outcomes in the context of heart failure (HF). Since heart failure with reduced ejection fraction (HFrEF) accounts for approximately 50% of cases in the general HF population, we aimed to evaluate the effect of insulin treatment on left ventricular (LV) remodeling and contractility abnormalities in a HFrEF cohort and assess whether insulin was a predictor of adverse outcomes in this entity.MethodsA total of 377 HFrEF patients who underwent cardiac MRI were included and divided according to diabetes status and the need for insulin treatment. LV structural and functional indices, as well as systolic strains, were measured. The determinants of impaired myocardial strains were assessed using linear regression analysis. The associated endpoints were determined using a multivariable Cox proportional hazards model.ResultsT2DM patients on insulin displayed a higher indexed LV end-diastolic volume and LV mass than those with T2DM not on insulin or those without T2DM, despite similar LV ejection fractions, accompanied by a higher three-dimensional spherical index (P < 0.01). Worse longitudinal and circumferential peak systolic strain was shown to occur in T2DM patients on insulin (P < 0.01). Insulin treatment was independently associated with impaired magnitudes of systolic strain. The median follow-up duration was 32.4 months (IQR, 15.6–43.2 months). Insulin treatment remained consistently associated with poor outcomes after adjustment for established confounders, with an adjusted hazard ratio of 3.11; (95% CI, 1.45–6.87; P = 0.009) in the overall cohort and 2.16 (95% CI, 1.08–4.59; P = 0.030) in the diabetes cohort.ConclusionsInsulin may further lead to adverse LV remodeling and contractile dysfunction in the context of HFrEF with T2DM. Considerable care should be taken when treating HFrEF patients with insulin.

Different Continuous Training Intensities Improve Echocardiographic Parameters, Quality of Life, and Functional Capacity in Heart Failure Patients with Reduced Ejection Fraction.

Multiple comorbidities and physiological changes play a role in a range of heart failure conditions and influence the most effective approach to exercise-based rehabilitation. This research aimed to examine and compare the outcomes of continuous training at three different intensities, focusing on left ventricular (LV) remodeling, functional capacity, and quality of life among patients with heart failure with reduced ejection fraction (HFrEF). In this randomized control trial, a total of 60 male patients (average age: 54.33 ±2.35 years) with HFrEF were randomly allocated into three groups: 1) High-intensity continuous training group (HICT), 2) Moderate-intensity continuous training group (MICT), and 3) Low-intensity continuous training group (LICT). All the training was performed on a bicycle ergometer 3 times/week for 12 weeks. Echocardiographic parameters (left ventricular ejection fraction, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, N-terminal pro-B-type natriuretic peptide (NT-proBNP), quality of life (Minnesota Living with Heart Failure Questionnaire), and functional capacity (6-minute walking test) were assessed before and the end of the study. The HICT group demonstrated the greatest improvements in all measured variables when compared to the other two groups (P < 0.05). These findings were consistent across all measured outcomes. It was determined that HICT appears to yield the most favorable outcomes in enhancing echocardiographic measures, NT-proBNP levels, quality of life, and functional capacity among HFrEF patients.

The effects of Digoxin use on long-term prognosis in patients with heart failure with reduced ejection fraction.

This study aimed to investigate the effect of digoxin on mortality and rehospitalization in heart failure with reduced ejection fraction (HFrEF) patients. Heart failure is a clinical syndrome that requires frequent rehospitalization and has a high mortality. This study aimed to investigate the effect of digoxin on mortality and rehospitalization in patients with heart failure with reduced ejection fraction. The study included 326 patients with HFrEF that were hospitalized for decompensation between September 2014 and January 2016. The patients were divided into two groups: digoxin users and a control group. The study's endpoints were cardiovascular death and rehospitalization after 24-month long-term follow-ups. Rehospitalization was lower in patients taking digoxin (25% vs. 47%, p = 0.001). The mean age of patients taking digoxin (n: 78) was 63.7 ± 12.4 years, among which 64% were males. The mean age of the control group was 65.4 ± 11.8 years, among which 74% were males. However, there was no difference in mortality between the two groups (34% vs. 45%, p = 0.10). While Kaplan-Meier curves revealed no significant differences between mortality rates in the groups (log-rank p = 0.508), a statistical difference was found between the groups in rehospitalization rates (log-rank p = 0.013). A multiple linear regression analysis revealed that smoking (HR: 1.97, CI: 1.24-3.11, p = 0.004), systolic blood pressure (HR: 0.983, CI: 0.974-0.992, p < 0.001), atrial fibrillation (HR: 2.09, CI: 1.17-3.72, p = 0.012), C-reactive protein (CRP) (HR: 1.009, CI: 1.003-1.015, p = 0.004), beta-blockers (HR: 0.891, CI: 0.799-0.972, p = 0.009), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (HR: 0.778, CI: 0.641-0.956, p < 0.001), mineralocorticoid receptor antagonists (HR: 0.41, CI:0.26-0.65, p < 0.001), and digoxin use (HR: 0.59, CI: 0.43-0.80, p = 0.001) are independent predictors of rehospitalization in patients with HFrEF. Our results show that digoxin use does not affect mortality in HFrEF patients. However, rehospitalization decreased in patients taking digoxin in HFrEF.

Exercise Oscillatory Ventilation Improves Heart Failure Prognostic Scores.

Several heart failure (HF) prognostic risk scores are available to guide the ideal time for listing candidates for a heart transplant (HTx). The detection of exercise oscillatory ventilation (EOV) during cardiopulmonary exercise testing (CPET) is associated with advanced HF and a worse prognosis, and yet it is not accounted for in these risk scores. Therefore, this study aimed to assess whether EOV further adds prognostic value to HF scores. A single-centre retrospective cohort study was undertaken of consecutive HF patients with reduced ejection fraction (HFrEF) who underwent CPET from 1996 to 2018. The Heart Failure Survival Score (HFSS), Seattle Heart Failure Model (SHFM), Meta-analysis Global Group In Chronic Heart Failure (MAGGIC), and Metabolic Exercise Cardiac Kidney Index (MECKI) were calculated. The added value of EOV on top of those scores was assessed using a Cox proportional hazard model. The added discriminative power was also assessed by receiver operating characteristic curve comparison. A total of 390 HF patients with a median age of 58 (IQR 50-65) years were investigated, of whom 78% were male and 54% had ischaemic heart disease. The median peak oxygen consumption was 15.7 mL/kg/min (IQR 12.8-20.1). Exercise oscillatory ventilation was detected in 153 (39.2%) patients. Over a median follow-up of 2 years, 61 patients died (49 due to a cardiovascular reason) and 54 had a HTx. Exercise oscillatory ventilation independently predicted the composite outcome of all-cause death and HTx. Furthermore, the presence of this ventilatory pattern significantly improved the prognostic performance of both HFSS and MAGGIC scores. Exercise oscillatory ventilation was often found in a cohort of HF patients with reduced LVEF who underwent CPET. It was found that EOV added further prognostic value to contemporary HF scores, suggesting that this easily obtained parameter should be included in future modified HF scores.

Different kinetics of NT-proBNP and sST2 highlight different therapeutic pathways of sacubitril/valsartan

Abstract Funding Acknowledgements Type of funding sources: None. Background N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. Both are potential targets of HFrEF treatment, but the first is associated with the patient’s hemodynamic status, while the second is more indicative of the inflammatory status and of myocardial fibrosis. Purpose The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF. Methods We analyzed blood samples of HFrEF patients at baseline (before sacubitril/valsartan treatment), after 1, 2, 3 months (respectively after a month taking the 24/26 – 49/51 – 97/103mg b.i.d. doses), and 6 months after the maximum tolerated dose was reached (end-study). Results We obtained samples from 72 HFrEF patients (age 64.0±10.5, 83% males) (Table 1). NT-proBNP and sST2 values progressively and significantly reduced up to 37% and 16%, respectively, with a greater reduction for NT-proBNP (p&amp;lt;0.001). Specifically, NT-proBNP reduced from 1144 [593-2586] to 743 [358-1524] pg/mL and sST2 from 27.3 [20.5-35.0] to 23.1 [15.9-30.7] ng/mL, p for trend &amp;lt;0.001 in both cases). The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP (Figure 1). No significant changes in renal function and potassium levels were recorded. Conclusions These findings suggest that, in HF patients, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic anti-inflammatory, delayed one. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.Table 1Figure 1

Sacubitril/valsartan improves exercise performance in patients with heart failure: a dose-dependent effect

Abstract Funding Acknowledgements Type of funding sources: None. Background Sacubitril/Valsartan therapy has become a cornerstone of heart failure with reduced ejection fraction (HFrEF) pharmacological therapy due to its positive prognostic impact. However, conflicting results have emerged on the effects of sacubitril/valsartan on exercise performance assessed by cardiopulmonary exercise test (CPET). Purpose The aim of this study was to prospectively evaluate the effects of sacubitril/valsartan on prognostically significant CPET parameters in a larger population of HFrEF patients at different drug doses. Methods We prospectively enrolled HFrEF outpatients eligible to start sacubitril/valsartan according to 2016 ESC Guidelines in 3 Heart Failure Units. Patients underwent CPET at baseline (before sacubitril/valsartan treatment), after 1, 2, 3 months (respectively after a month taking the 24/26 – 49/51 – 97/103mg doses), and 6 months after the maximum tolerated dose was reached (end-study). The subjective impression of disease-related limitation was assessed using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). Results 113 patients were enrolled (age 64.5±9.7, 81% males) (Table 1). Peak oxygen intake (peakVO2) improved at each step from 15.0±4.5 mL/min/kg at baseline to 16.5±4.9 mL/min/kg at end study visit, corresponding to 61.5±16.0 and 67.9±17.4 % of predicted, respectively (p&amp;lt;0.05). Minute ventilation/carbon dioxide production relationship (VE/VCO2 slope) reduced from 39.6±5.5 to 35.9±7.1 (p = 0.005) in the 39 patients (42%) with pathological VE/VCO2≥34 at baseline. KCCQ improved significantly since the first visit with an overall summary score increase from 47.9±11.1 to 52.6±9.8 (p&amp;lt;0.001). Conclusions These findings suggest that sacubitril/valsartan benefits on exercise capacity are immediately evident at the lowest dose and progressively improve as the dose increases.

A network medicine approach to study comorbidities in heart failure with preserved ejection fraction

BackgroundComorbidities are expected to impact the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, comorbidity profiles are usually reduced to a few comorbid disorders. Systems medicine approaches can model phenome-wide comorbidity profiles to improve our understanding of HFpEF and infer associated genetic profiles.MethodsWe retrospectively explored 569 comorbidities in 29,047 HF patients, including 8062 HFpEF and 6585 HF with reduced ejection fraction (HFrEF) patients from a German university hospital. We assessed differences in comorbidity profiles between HF subtypes via multiple correspondence analysis. Then, we used machine learning classifiers to identify distinctive comorbidity profiles of HFpEF and HFrEF patients. Moreover, we built a comorbidity network (HFnet) to identify the main disease clusters that summarized the phenome-wide comorbidity. Lastly, we predicted novel gene candidates for HFpEF by linking the HFnet to a multilayer gene network, integrating multiple databases. To corroborate HFpEF candidate genes, we collected transcriptomic data in a murine HFpEF model. We compared predicted genes with the murine disease signature as well as with the literature.ResultsWe found a high degree of variance between the comorbidity profiles of HFpEF and HFrEF, while each was more similar to HFmrEF. The comorbidities present in HFpEF patients were more diverse than those in HFrEF and included neoplastic, osteologic and rheumatoid disorders. Disease communities in the HFnet captured important comorbidity concepts of HF patients which could be assigned to HF subtypes, age groups, and sex. Based on the HFpEF comorbidity profile, we predicted and recovered gene candidates, including genes involved in fibrosis (COL3A1, LOX, SMAD9, PTHL), hypertrophy (GATA5, MYH7), oxidative stress (NOS1, GSST1, XDH), and endoplasmic reticulum stress (ATF6). Finally, predicted genes were significantly overrepresented in the murine transcriptomic disease signature providing additional plausibility for their relevance.ConclusionsWe applied systems medicine concepts to analyze comorbidity profiles in a HF patient cohort. We were able to identify disease clusters that helped to characterize HF patients. We derived a distinct comorbidity profile for HFpEF, which was leveraged to suggest novel candidate genes via network propagation. The identification of distinctive comorbidity profiles and candidate genes from routine clinical data provides insights that may be leveraged to improve diagnosis and identify treatment targets for HFpEF patients.Graphical

Efficacy of sacubitril-valsartan and SGLT2 inhibitors in heart failure with reduced ejection fraction: A systematic review and meta-analysis.

Sacubitril-valsartan (SV) monotherapy has been shown to help patients with Heart failure with reduced ejection fraction (HFrEF), but whether adding a sodium-glucose cotransporter-2 inhibitor (SGLT2i) improves treatment results even more is unknown. The goal of this study was to look at the efficacy of SV with additional SGLT2i in HFrEF patients. For this study, several databases, such as PubMed, EMBASE, Web of Science, and the Cochrane Library, were searched. A coherent search approach was used for data extraction. Review Manager 5.2 and MedCalc were used for conducting the meta-analysis and bias analysis. A meta-regression study correlates patient mean age with primary and secondary outcomes. Seven trials totaling 16 100 patients were included in this meta-analysis. All-cause mortality, cardiovascular mortality, and improvement in mean left ventricular ejection fraction (LVEF) were the study's major objectives, while hospitalization for heart failure (HF) was calculated to be its secondary outcome. Our analysis showed that HFrEF patients receiving the combination of SV and SGLT2i had better treatment outcomes than the standard SV monotherapy, with risk ratios of 0.76 (0.65-0.88) for all-cause mortality, 0.65 (0.49-0.86) for cardiovascular mortality, 1.41 (-0.59 to 3.42) for change in mean LVEF, and 0.80 (0.64-1.01) for hospitalization for HF. According to the regression analysis, older HFrEF patients have higher rates of hospitalization, cardiovascular disease, and overall death. The combination of SV and SGLT2i may have a greater cardiovascular protective effect and minimize the risk of death or hospitalization due to heart failure in HFrEF.

Haemodynamic forces predicting remodelling and outcome in patients with heart failure treated with sacubitril/valsartan.

A novel tool for the evaluation of left ventricular (LV) systo-diastolic function through echo-derived haemodynamic forces (HDFs) has been recently proposed. The present study aimed to assess the predictive value of HDFs on (i) 6month treatment response to sacubitril/valsartan in heart failure with reduced ejection fraction (HFrEF) patients and (ii) cardiovascular events. Eighty-nine consecutive HFrEF patients [70% males, 65±9years, LV ejection fraction (LVEF) 27±7%] initiating sacubitril/valsartan underwent clinical, laboratory, ultrasound and cardiopulmonary exercise testing evaluations. Patients experiencing no adverse events and showing ≥50% reduction in plasma N-terminal pro-B-type natriuretic peptide and/or ≥10% LVEF increase over 6months were considered responders. Patients were followed up for the composite endpoint of HF-related hospitalisation, atrial fibrillation and cardiovascular death. Forty-five (51%) patients were responders. Among baseline variables, only HDF-derived whole cardiac cycle LV strength (wLVS) was higher in responders (4.4±1.3 vs. 3.6±1.2; p=0.01). wLVS was also the only independent predictor of sacubitril/valsartan response at multivariable logistic regression analysis [odds ratio 1.36; 95% confidence interval (CI) 1.10-1.67], with good accuracy at receiver operating characteristic (ROC) analysis [optimal cutpoint: ≥3.7%; area under the curve (AUC)=0.736]. During a 33month (23-41) median follow-up, a wLVS increase after 6months (ΔwLVS) showed a high discrimination ability at time-dependent ROC analysis (optimal cut-off: ≥0.5%; AUC=0.811), stratified prognosis (log-rank p<0.0001) and remained an independent predictor for the composite endpoint (hazard ratio 0.76; 95% CI 0.61-0.95; p<0.01), after adjusting for clinical and instrumental variables. HDF analysis predicts sacubitril/valsartan response and might optimise decision-making in HFrEF patients.

Sacubitril/valsartan effects on arrhythmias and left ventricular remodelling in heart failure: An observational study

AimsConflicting results have been reported in the literature on the potential antiarrhythmic effect of sacubitril/valsartan in heart failure patients with reduced ejection fraction (HFrEF). The objectives of this study were: 1- to evaluate the long term effects of sacubitril/valsartan on arrhythmic burden in HFrEF patients; 2- to evaluate the correlation between the reduction of premature ventricular complexes during f-up and reverse remodelling. MethodsWe identified 255 consecutive HFrEF patients treated with sacubitril/valsartan between March 2017 and May 2020 and followed by the Heart Failure and Cardiac Transplant Unit of IRCCS San Matteo Hospital in Pavia (Italy). Within this subgroup, 153 patients underwent 24 h-Holter-ECG or implantable cardioverter defibrillators (ICD) interrogation at baseline, at 12 months (t1) and at 24 months (t2) and transthoracic echocardiography at baseline and after 12 months after the beginning of sacubitril/valsartan. Cardiac-related hospitalizations were analyzed in the 12 months preceding and during 24 months following the drug starting date. ResultsGlobal burden of 24-h premature ventricular complexes (PVC) was significantly reduced at 12 months (t1) and at 24 months (t2) as compared to the same period before treatment (1043 [304–3360] vs 768 [82–2784] at t1 vs 114 [9–333] at t2, P = 0.000). In the subgroup of patients implanted with biventricular ICD (n = 30), the percentage of biventricular pacing increased significantly (96% [94–99] vs 98% [96–99] at t1 vs 98%[97–100] at t2; P = 0.027). The burden of non-sustained ventricular tachycardia and sustained ventricular tachycardia did not change from baseline to t1 and t2, but a reduction of patients with at least one ICD appropriate shock was reported. The correlations between reduction in 24 h PVC and reduction in LV-ESVi or improvement in LVEF were not statistically significant (respectively R = 0.144, P = 0.197 and R = -0.190, P = 0.074). Heart failure related hospitalizations decreased during follow up (11.1% in the year before treatment vs 4.6% at t1 and 4.6% at t2; P = 0.040). ConclusionSacubitril/valsartan reduced the number of premature ventricular complexes and increased the percentage of biventricular pacing in a cohort of HFrEF patients already on optimal medical therapy. PVC reduction did not correlate with reverse left ventricular remodelling. Whether sacubitril/valsartan has any direct antiarrhythmic effects is an issue to be better explored in future studies.

Effects of Angiotensin Receptor-Neprilysin Inhibitors Versus Enalapril or Valsartan on Patients With Heart Failure: A Systematic Review and Meta-Analysis.

Recent studies have focused on treating heart failure, primarily mitigating symptoms and reducing the risk of mortality and other cardiovascular complications. A promising new treatment approach involves using LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI) comprising sacubitril and valsartan. This treatment is superior to the conventional drugs enalapril or valsartan in patients diagnosed with heart failure. A systematic search was conducted on PubMed, the Cochrane Library, and Elsevier's ScienceDirect databases to identify studies comparing sacubitril/valsartan with other drugs in heart failure patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The analyses were conducted using the random-effects model. The study's primary outcomes included all-cause mortality, death from cardiovascular causes, first hospitalization for heart failure, congestive heart failure, and changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical score. The pooled analysis showed that treatment with the sacubitril/valsartan combination was associated with a significantly decreased rate of first hospitalization for heart failure (RR: 0.86; 95% CI: 0.79, 0.98, p: 0.03; I2: 57%) and significantly increased KCCQ clinical score (WMD: 2.20; 95% CI: 0.33, 4.06, p: 0.02; I2: 100%). However, the two groups had no significant difference in all-cause mortality (RR: 0.90; 95% CI: 0.80, 1.01, p: 0.08; I2: 20%), death from cardiovascular causes (RR: 0.96; 95% CI: 0.87, 1.05, p: 0.34; I2: 0%), or congestive heart failure (RR: 0.97; 95% CI: 0.75, 1.25, p: 0.19; I2: 38%). The research findings suggest that sacubitril/valsartan (LCZ696) reduces hospitalizations due to heart failure and improves KCCQ clinical scores. This treatment also reduces the decline in renal function and side effects associated with enalapril or valsartan. Nonetheless, further high-quality randomized controlled trials with large sample sizes are needed to assess other impacts of this therapy on heart failure patients. Overall, the use of LCZ696 represents a promising new approach to the treatment of heart failure.

Financial burden of heart failure in Malaysia: A perspective from the public healthcare system.

Estimating and evaluating the economic burden of HF and its impact on the public healthcare system is necessary for devising improved treatment plans in the future. The present study aimed to determine the economic impact of HF on the public healthcare system. The annual cost of HF per patient was estimated using unweighted average and inverse probability weighting (IPW). Unweight average estimated the annual cost by considering all observed cases regardless of the availability of all the cost data, while IPW calculated the cost by weighting against inverse probability. The economic burden of HF was estimated for different HF phenotypes and age categories at the population level from the public healthcare system perspective. The mean (standard deviation) annual costs per patient calculated using unweighted average and IPW were USD 5,123 (USD 3,262) and USD 5,217 (USD 3,317), respectively. The cost of HF estimated using two different approaches did not differ significantly (p = 0.865). The estimated cost burden of HF in Malaysia was USD 481.9 million (range: USD 31.7 million- 1,213.2 million) per year, which accounts for 1.05% (range: 0.07%-2.66%) of total health expenditure in 2021. The cost of managing patients with heart failure with reduced ejection fraction (HFrEF) accounted for 61.1% of the total financial burden of HF in Malaysia. The annual cost burden increased from USD 2.8 million for patients aged 20-29 to USD 142.1 million for those aged 60-69. The cost of managing HF in patients aged 50-79 years contributed 74.1% of the total financial burden of HF in Malaysia. A large portion of the financial burden of HF in Malaysia is driven by inpatient costs and HFrEF patients. Long-term survival of HF patients leads to an increase in the prevalence of HF, inevitably increasing the financial burden of HF.

Effect of Angiotensin Receptor-Neprilysin Inhibitor on Cardiac Remodeling in Heart Failure with Reduced Ejection Fraction in Kuwait

Abstract Background: Heart failure with reduced ejection fraction (HFrEF) is a growing concern in the Middle East and worldwide, despite advances in treatment. The introduction of angiotensin receptor-neprilysin inhibitor (ARNI) has shown promise in managing HFrEF by inhibiting the renin–angiotensin–aldosterone system. However, its effects on cardiac remodeling and outcomes in the Middle East are poorly understood. Objectives: To determine the effectiveness and safety of ARNI in improving outcomes for HFrEF patients in Kuwait. Methods: This observational study, conducted at Al Dabbous Cardiac Center in Kuwait, included 114 adult HFrEF patients treated with ARNI for 6 months. Data on patient characteristics, echocardiographic measurements, and clinical parameters were collected before and after treatment. Statistical analysis was performed using paired t-tests and nonparametric sign tests. Results: Following ARNI treatment, significant improvements were observed in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), right ventricular systolic pressure (RVSP), and New York Heart Association Functional Classification. LVEF increased from 29.54% to 32.22% (P &lt; 0.001). LVEDD and RVSP decreased significantly (P &lt; 0.001, P = 0.016, respectively), while systolic blood pressure decreased (P = 0.002). The study showed no significant changes in weight or potassium levels. Adverse effects were minimal. Conclusions: This study contributes to the growing body of evidence supporting ARNI’s effectiveness in improving outcomes for HFrEF patients, particularly in a Middle Eastern population. ARNI treatment resulted in significant improvements in cardiac remodeling and clinical parameters, emphasizing its potential as a valuable therapeutic option for HFrEF patients. Additional research is essential to optimize ARNI’s use and enhance patient outcomes.