Heart Failure Drug Research Articles

Real-world use of sodium-glucose co-transporter 2 inhibitors in patients with heart failure and reduced ejection fraction: Data from the Swedish Heart Failure Registry.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) reduce mortality/morbidity in heart failure (HF). We explored the implementation of SGLT2i over time, and patient characteristics associated with their use, in a large, nationwide population with HF with reduced ejection fraction (HFrEF). Patients with HFrEF (EF < 40%), no type1 diabetes, estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 and/or on dialysis, registered in the Swedish HF Registry between 1-November-2020 and 5-August-2022 were included. Independent predictors of use were investigated by multivariable logistic regressions. Of 8192 patients, 37% received SGLT2i. Use increased overall from 20.5% to 59.0% over time, from 46.2% and 12.5% to 69.8% and 55.4% in patients with and without type 2 diabetes (T2DM), from 14.7% and 22.3% to 58.0% and 59.8% in eGFR<60 vs. ≥60 mL/min/1.73m2 , from 21.6% and 18.9% to 61.6% and 52.0% in males vs. females, from 24.2% and 18.0% to 60.8% and 57.7% in patients with vs. without recent HF hospitalization, from 26.1% and 19.8% to 54.7% and 59.6% in in- vs. out-patient, and from 20.2% and 21.2% to 59.2% and 58.7% in those with HF duration < vs ≥6 months, respectively. Important characteristics associated with SGLT2i use were male sex, recent HF hospitalization, specialized HF follow-up, lower EF, T2DM, higher education level, use of other HF/cardiovascular interventions. Older age, higher blood pressure, atrial fibrillation and anemia were associated with less use. Discontinuation rate at 6 and 12 months was 13.1% and 20.0%, respectively. Use of SGLT2i increased 3-fold over 2 years. Although this indicates a more rapid translation of trials results and guidelines into clinical practice compared to previous HF drugs, further efforts are advocated to complete the implementation process while avoiding inequities across different patients' subgroups and discontinuations. This article is protected by copyright. All rights reserved.

Guideline-Directed Medical Therapies for Heart Failure with a Reduced Ejection Fraction in Older Adults: A Narrative Review on Efficacy, Safety and Timeliness.

Heart failure is a prevalent syndrome among older adults, with a major impact on morbidity and mortality. Higher age is correlated with underuse of guideline-directed medical therapies which, in turn, has been linked to worse clinical outcomes. Importantly, most evidence so far has been collected in adults who were younger, less multi-morbid and polymedicated compared with those who are commonly treated in daily clinical practice. Hence, we aimed to assess and describe the evidence base for pharmacotherapy in older adults with heart failure with a reduced ejection. First, a narrative review was undertaken using Medline, from inception to January 2023. Four foundational therapies were selected based on the latest European Society of Cardiology clinical practice guideline: angiotensin-converting enzyme inhibitors/angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 inhibitors. Post hoc analyses from landmark heart failure drug trials were searched and included if they contained data on the impact of age on efficacy, safety and/or timeliness of therapies in the management of heart failure with a reduced ejection fraction. Second, a proposal was developed to support and promote the use of evidence-based heart failure pharmacotherapy in complex, older adults. In total, 11 articles were selected: 4 meta-analyses, 6 post hoc analyses and 1 review paper. No attenuation of efficacy for any of the foundational agents was found in older adults. Regarding safety, dedicated analyses showed that beta blockers, mineraloid receptor antagonists, sacubitril-valsartan, dapagliflozin and empagliflozin retained their overall benefit-risk profile regardless of age. Time to benefit was short and occurred generally within 1 month. Consensus was achieved on a five-step proposal to manage complex medication regimens in older adults suffering from heart failure. In conclusion, older adults suffering from heart failure with a reduced ejection fraction should not be denied treatment based on their age.

Sacubitril/valsartan for cardioprotection in breast cancer (MAINSTREAM): design and rationale of the randomized trial.

In recent years, survival in patients with breast cancer has increased. Despite the improvement in outcomes of those patients, the risk of treatment-related cardiotoxicity remains high, and its presence has been associated with a higher risk of treatment termination and thus lower therapeutic efficacy. Prior trials demonstrated that a preventive initiation of heart failure drugs, including the renin-angiotensin-aldosterone inhibitors, might reduce the risk of treatment-related cardiotoxicity. However, to date, no study investigated the efficacy of sacubitril/valsartan, a novel antineurohormonal drug shown to be superior to the previous therapies, in the prevention of cardiotoxicity in patients with early-stage breast cancer, which is the aim of the trial. MAINSTREAM is a randomized, placebo-controlled, double-blind, multicentre, clinical trial. After the run-in period, a total of 480 patients with early breast cancer undergoing treatment with anthracyclines and/or anti-human epidermal growth factor receptor 2 drugs will be randomized to the highest tolerated dose of sacubitril/valsartan, being preferably 97/103mg twice daily or placebo in 1:1 ratio. The patients will be monitored, including routine transthoracic echocardiography (TTE) and laboratory biomarker monitoring, for 24months. The primary endpoint of the trial will be the occurrence of a decrease in left ventricular ejection fraction by ≥5% in TTE within 24months. The key secondary endpoints will be the composite endpoint of death from any cause or hospitalization for heart failure, as well as other imaging, laboratory, and clinical outcomes, including the occurrence of the cancer therapy-related cardiac dysfunction resulting in the necessity to initiate treatment. The first patients are expected to be recruited in the coming months, and the estimated completion of the study and publication of the results are expected in December 2027, pending recruitment. The MAINSTREAM trial will determine the efficacy and safety of treatment with sacubitril/valsartan as a prevention of cardiotoxicity in patients with early breast cancer (ClinicalTrials.gov number: NCT05465031).

Cardiomyopathy as cause of death in Duchenne muscular dystrophy: a longitudinal observational study.

Cardiomyopathy has become an important life-limiting factor since survival in Duchenne muscular dystrophy (DMD) has greatly increased with long-term ventilation and cough assistance. The aim of this study was to investigate the association between impaired left ventricular ejection fraction (LVEF) and survival. In a >20-year observational study in patients with DMD (age ≥16 years) with at least three echocardiograms, the association between LVEF and survival and time to cardiac or non-cardiac death was investigated using Kaplan-Meier survival analysis and Cox regression (for LVEF). In 67 DMD patients (430 echocardiograms), the decrease in LVEF over a mean±sd follow-up period of 9.1±5.1 years was -10.0±13.9% absolute, but LVEF progression varied widely. 84% were receiving an angiotensin-converting enzyme inhibitor and 54% a β-blocker at last follow-up with an LVEF of 37.5±12.4% at that time-point. Median (interquartile range) survival was 33 (25-40) years. 28 out of 67 (42%) of the cohort had died and LVEF was a significant negative predictor of survival (hazard ratio 0.95 (95% CI 0.91-0.99); p<0.007). Those who died of cardiac death (53% of known causes of death) had significantly lower LVEF at the time of death (LVEF -11.0% (95% CI -21.1- -0.9%); p=0.035) compared with non-cardiac death and tended to die at a younger age. Cardiomyopathy with systolic heart failure is the leading cause of death and lower LVEF is an independent predictor of mortality at younger ages in patients with DMD. Patients with DMD appear to be undertreated with respect to heart failure drug therapy.

Vericiguat preserved cardiac function and mitochondrial quality in a rat model of mitral regurgitation

AimsNew drugs for heart failure (HF) that target restoring the impaired NO-sGC-cGMP pathway are being developed. We aimed to investigate the effects of vericiguat, an sGC stimulator, on cardiac function, blood pressure (BP), cardiac mitochondrial quality, and cardiac fibrosis in rat models of chronic mitral regurgitation (MR). Materials and methodsWe surgically induced MR in 20 Sprague-Dawley rats and performed sham procedures on 10 rats (negative control). Four weeks post-surgery, we randomly divided the MR rats into two groups: MR group and MR + vericiguat group. Vericiguat (0.5 mg/kg, PO) was administered once a day via oral gavage for 8 weeks, while the sham and MR groups received equivalent volumes of drinking water instead. We took echocardiography and BP measurements at baseline (4 weeks post-surgery) and at the end of study (8 weeks after treatment). At the study end, all rats were euthanized and their hearts were immediately collected, weighed, and used for histopathology and mitochondrial quality assessments. Key findingsVericiguat preserved cardiac functions and structural remodeling in the MR rats, with significantly lower systolic BPs than baseline values (P < 0.05). Additionally, vericiguat significantly improved the mitochondrial quality by attenuating ROS production, depolarization and swelling when comparing the values in both groups (P < 0.05). The fibrosis area also significantly decreased in the MR + vericiguat group (P < 0.05). SignificanceVericiguat demonstrated cardioprotective effects on cardiac function, BP, and fibrosis by preserving mitochondrial quality in rats with HF due to MR.

Heart Failure Therapies following Acute Coronary Syndromes with Reduced Ejection Fraction: Data from the ACSIS Survey.

Guideline-directed medical therapies for heart failure (HF) may benefit patients with reduced left ventricular ejection fraction (LVEF) following acute coronary syndromes (ACS). Few real-world data are available regarding the early implementation of HF therapies in patients with ACS and reduced LVEF. Data collected from the 2021 nationwide, prospective ACS Israeli Survey (ACSIS). Drug classes included: (a) angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNI); (b) beta-blockers; (c) mineralocorticoid receptor antagonist (MRA) and (d) sodium-glucose cotransporter-2 inhibitors (SGLT2I). The utilization of HF therapies at discharge or 90 days following ACS was analyzed in relation to LVEF [reduced ≤40% (n = 406) or mildly-reduced 41-49% (n = 255)] and short-term adverse outcomes. History of HF, anterior wall myocardial infarction and Killip class II-IV (32% vs. 14% p < 0.001) were more prevalent in those with reduced compared to mildly-reduced LVEF. ACEI/ARB/ARNI and beta-blockers were used by the majority of patients in both LVEF groups, though ARNI was prescribed to only 3.9% (LVEF ≤ 40%). MRA was used by 42.9% and 12.2% of patients with LVEF ≤40% and 41-49%, respectively, and SGLT2I in about a quarter of both LVEF groups. Overall, ≥3 HF drug classes were documented in 44% of the patients. A trend towards higher rates of 90-day HF rehospitalizations, recurrent ACS or all-cause death was noted in those with reduced (7.6%) vs. mildly-reduced (3.7%) LVEF, p = 0.084. No association was observed between the number of HF drug classes or the use of ARNI and/or SGLT2I with adverse clinical outcomes. In current clinical practice, the majority of patients with reduced and mildly-reduced LVEF are treated by ACEI/ARB and beta-blockers early following ACS, whereas MRA is underutilized and the adoption of SGLT2I and ARNI is low. A greater number of therapeutic classes was not associated with reduced short-term rehospitalizations or mortality.

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

POINT: Should New Drug Development in Heart Failure Focus on Patients Discharged From an Acute Heart Failure Admission? Lessons From Recent Studies

POINT: Should New Drug Development in Heart Failure Focus on Patients Discharged From an Acute Heart Failure Admission? Lessons From Recent Studies

#6869 CARDIAC ALTERATIONS FOUND IN PATIENTS WHO START DIALYSIS

Abstract Background and Aims The presence of cardiac structural alterations in patients with chronic kidney disease who start renal replacement therapy is frequent. In fact, the real prevalence of heart failure is not well known due to the masking of symptoms by frequent ultrafiltration. Despite this, most deaths in these patients occur due to cardiovascular events, especially non-atheroembolic events, which are closely related to heart failure and ventricular remodeling. This study aimed to describe the echocardiographic alterations present in patients who start renal replacement therapy. Method Cross-sectional study to evaluate the prevalence of structural abnormalities in transthoracic echocardiography performed in patients at the time of initiating renal replacement therapy in the prevalent group of patients in kidney replacement therapy program at Hospital Clínic de Barcelona. Demographic variables and baseline drugs for heart failure were also collected. Results We included 170 patients of 67.84 ± 15.92 years. 115 (67.6%) were men, and 55 were women (32.4%). Of these, 124 (72.9%) were on hemodialysis, 11 (6.5%) on home hemodialysis, and 35 (20.6%) on peritoneal dialysis. Transthoracic echocardiogram findings at the beginning of dialysis showed a left ventricular ejection fraction of 47.5 ± 10.6%. It was reduced in 21 (12.4%), slightly reduced in 9 (5.3%) and preserved in 125 (73.5%) of the patients. The estimated pulmonary artery systolic pressure was 28.5 ± 3.53 mmHg. The telediastolic diameter of the left ventricle was 5.5 ± 0.71 cm, that of the interventricular septum was 1.15 ± 0.27 cm, the diameter of the left atrium was 4.5 ± 1.27 cm, its volume was 95.05 ± 56.5 mL in the biplane section and 54.3 ± 28.28 mL in the four-chamber section. There were no significant differences between groups when analyzed by type of renal replacement therapy. Regarding valvulopathies, 47 (21.8%) had some degree of aortic stenosis, 68 (40%) had some degree of aortic insufficiency, 104 (62.2%) had some degree of tricuspid insufficiency, 118 (69.4%) some degree of mitral insufficiency. Regarding treatment, 50 (29.4%) of the patients had some RAASi, 60 (35.3%) had beta-blockers, and 2 (1.2%) had MRA. Conclusion The presence of structural alterations in the heart of patients initiating renal replacement therapy is practically universal and independent of the type of technique initiated. Nephrologists should become aware of these findings and seek ways to prevent and reverse these alterations as far as possible to achieve better clinical results in dialysis.

Parenteral Nutrition, Sepsis, Acute Heart Failure and Hepatotoxic Drugs Are Related to Liver Test Disturbances in Critically Ill Patients.

Parenteral nutrition (PN) is often associated with liver dysfunction in the ICU, although other factors such as sepsis, acute heart failure (AHF), and hepatotoxic drugs can be equally present. The relative impact of PN on liver dysfunction in critically ill patients is largely unknown. We recorded the presence of pre-existing liver disturbances, AHF, sepsis, daily PN volume, and commonly used hepatotoxic drugs in adult ICU patients, together with daily aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), alkalic phosphatase (AP), total bilirubin (TB), and INR values in patients with three or more PN treatment days. A linear mixed-effects model was used to assess the relative contribution of each liver parameter. Nutritional adequacy was defined as intake/needs. We included 224 ICU patients with PN treatment lasting more than 3 days between 1 January 2017 and 31 December 2019. For AST, pre-existing liver disturbances (+180% ± 11%) and the presence of AHF (+75% ± 14%) were the main predictors of deterioration, whereas PN volume caused only a limited increase of 14% ± 1%/L. Similar results were observed for ALT. GGT, INR, and TB are mainly influenced by the presence of sepsis/septic shock and pre-existing liver disturbances, with no impact of PN or hepatotoxic drugs. Carbohydrate intake exceeded recommendations, and protein and lipid intake were insufficient in this study cohort. Liver test disturbances in ICU patients on PN are multifactorial, with sepsis and AHF having the highest influence, with only limited impact from PN and hepatotoxic drugs. Feeding adequacy can be improved.

Cardiac Resynchronization Therapy: current guidelines and recent advances beyond drug treatment.

Cardiac resynchronization therapy (CRT) is the therapy of choice for patients with symptomatic systolic heart failure (HF) and left bundle branch block (LBBB), despite optimal medical therapy (OMT). The recently published 2021 European Society of Cardiology (ESC) Guidelines on cardiac pacing and cardiac resynchronization therapy highlight the importance of CRT on top of OMT in HF patients with left ventricular ejection fraction (LVEF) ≤ 35%, sinus rhythm and typical LBBB with QRS duration ≥150ms. In the presence of medically intractable or recurrent after catheter ablation atrial fibrillation (AF), AV nodal ablation as an adjuvant therapy becomes more relevant in patients qualifying for the implantation of a biventricular system. Furthermore, CRT may be considered in cases when increased pacing of the right ventricle is not desirable. However, alternative pacing sites and strategies are currently available, if the CRT is not feasible and effective in patients. However, strategies targeting "multi-sides" or using "multi-leads" have shown superiority over classic CRT. On the other hand, conduction system pacing seems to be a promising technique. Although early results are positive, consistency during the long term is pending. The indication for additional defibrillation therapy (ICD) may occasionally be unnecessary and has to be considered individually. Due to the great development and success of heart failure drug therapy, its positive effect on LV function can lead to enormous improvement. Physicians must await these effects and findings, which hopefully could lead to a relevant LV improvement resulting in a definitive decision against an ICD.

ANMCO position paper on vericiguat use in heart failure: from evidence to place in therapy.

In the growing therapeutic armamentarium for heart failure (HF) management, vericiguat represents an innovative therapeutic option. The biological target of this drug is different from that of other drugs for HF. Indeed, vericiguat does not inhibit neuro-hormonal systems overactivated in HF or sodium-glucose co-transporter 2 but stimulates the biological pathway of nitric oxide and cyclic guanosine monophosphate, which is impaired in patients with HF. Vericiguat has recently been approved by international and national regulatory authorities for the treatment of patients with HF and reduced ejection fraction who are symptomatic despite optimal medical therapy and have worsening HF. This ANMCO position paper summarises key aspects of vericiguat mechanism of action and provides a review of available clinical evidence. Furthermore, this document reports use indications based on international guideline recommendations and local regulatory authority approval at the time of writing.

Neocryptotanshinone ameliorates insufficient energy production in heart failure by targeting retinoid X receptor alpha

Retinoid X receptor alpha (RXRα) is a nuclear transcription factor that extensively regulates energy metabolism in cardiovascular diseases. Identification of targeted RXRα drugs for heart failure (HF) therapy is urgently needed. Neocryptotanshinone (NCTS) is a component derived from Salvia miltiorrhiza Bunge, the effect and mechanism of which for treating HF have not been reported. The goal of this study was to explore the pharmacological effects of NCTS on energy metabolism to protect against HF post-acute myocardial infarction (AMI) via RXRα. We established a left anterior descending artery ligation-induced HF post-AMI model in mice and an oxygen-glucose deprivation-reperfusion-induced H9c2 cell model to investigate the cardioprotective effect of NCTS. Component–target binding techniques, surface plasmon resonance (SPR), microscale thermophoresis (MST) and small interfering RNA (siRNA) transfection were applied to explore the potential mechanism by which NCTS targets RXRα. The results showed that NCTS protects the heart against ischaemic damage, evidenced by improvement of cardiac dysfunction and attenuation of cellular hypoxic injury. Importantly, the SPR and MST results showed that NCTS has a high binding affinity for RXRα. Meanwhile, the critical downstream target genes of RXRα/PPARα, which are involved in fatty acid metabolism, including Cd36 and Cpt1a, were upregulated under NCTS treatment. Moreover, NCTS enhanced TFAM levels, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate levels by activating RXRα. In conclusion, we confirmed that NCTS improves myocardial energy metabolism, including fatty acid oxidation and mitochondrial biogenesis, by regulating the RXRα/PPARα pathway in mice with HF post-AMI.

Changes in the gut microbiota structure and function in rats with doxorubicin-induced heart failure.

The rat model of heart failure (HF) induced by doxorubicin (DOX), a broad spectrum and highly effective chemotherapeutic anthracycline with high-affinity to myocardial tissue that causes severe dose-dependent irreversible cardiotoxicity has been widely recognized and applied in HF pathogenesis and drug therapy studies. The gut microbiota (GM) has attracted significant attention due to its potential role in HF, and research in this area may provide beneficial therapeutic strategies for HF. Considering the differences in the route, mode, and total cumulative dose of DOX administration used to establish HF models, the optimal scheme for studying the correlation between GM and HF pathogenesis remains to be determined. Therefore, focusing on establishing the optimal scheme, we evaluated the correlation between GM composition/function and DOX-induced cardiotoxicity (DIC). Three schemes were investigated: DOX (at total cumulative doses of 12, 15 or 18 mg/kg using a fixed or alternating dose via a tail vein or intraperitoneal injection) was administered to Sprague Dawley (SD) for six consecutive weeks. The M-mode echocardiograms performed cardiac function evaluation. Pathological changes in the intestine were observed by H&E staining and in the heart by Masson staining. The serum levels of N-terminal pre-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) were measured by ELISA. The GM was analysed by 16S rRNA gene sequencing. Strikingly, based on the severity of cardiac dysfunction, there were marked differences in the abundance and grouping of GM under different schemes. The HF model established by tail vein injection of DOX (18 mg/kg, alternating doses) was more stable; moreover, the degree of myocardial injury and microbial composition were more consistent with the clinical manifestations of HF. The model of HF established by tail vein injection of doxorubicin, administered at 4mg/kg body weight (2mL/kg) at weeks 1, 3 and 5, and at 2mg/kg body weight (1mL/kg) at weeks 2, 4 and 6, with a cumulative total dose of 18mg/kg, is a better protocol to study the correlation between HF and GM.

Effects of dapagliflozin on cardiac function indexes and serum MCP-1 levels in patients with Type 2 diabetes mellitus complicated with heart failure

ABSTRACT Type 2 diabetes mellitus (T2DM) and heart failure (HF) are common in clinic, and they often coexist, triggering poor prognosis of patients and increasing hospitalization rates and mortality. Due to some common pathophysiological mechanisms between T2DM and HF, the two have synergistic effects and require collaborative management . In terms of the treatment of T2DM combined with HF, the effects of drugs on both diseases need to be considered to prevent the impact of HF drugs on glycometabolism. As an SGLT2 inhibitor, dapagliflozin can excrete glucose through the kidneys, reduce blood volume, decrease cardiac load to some extent, improve HF symptoms, and better control blood glucose . Therefore, this study selected 60 HF patients complicated with T2DM as the research subjects, and divided them into control group (CLG, conventional medical treatment) and observation group (ONG, dapagliflozin treatment) to explore the effects of dapagliflozin through comparative analysis. According to the results, compared with CLG, ONG had better improvement of blood glucose, cardiac function, and serum levels (P < 0.05), and a lower rehospitalization rate (P < 0.05), with no obvious between-group differences in the incidence of hypotension and emaciation (P > 0.05). These results showed that dapagliflozin in the treatment of T2DM with HF can improve blood glucose levels, cardiac function indexes and inflammatory factor levels, and decrease rehospitalization rates, presenting good clinical efficacy.

Cardiovascular Effect of Epoprostenol and Intravenous Cardiac Drugs for Acute Heart Failure on Canine Pulmonary Hypertension.

Pulmonary hypertension (PH) is a life-threatening complication in dogs with cardiopulmonary disease. Epoprostenol is an intravenous pulmonary vasodilator used to treat PH in humans; however, its efficacy in dogs remains unknown. We investigated the cardiovascular effects of epoprostenol and several cardiac agents for acute heart failure in canine models of chronic PH. Six dogs with chronic PH were anesthetized and underwent right heart catheterization and echocardiography before and after infusion of epoprostenol, dobutamine, dopamine and pimobendane. (The drug administration order was the same for all dogs). High-dose epoprostenol (15-20 ng/kg/min) tended to decrease pulmonary arterial pressure (PAP) while significantly decreasing pulmonary and systemic vascular resistance and increasing left and right ventricular (LV and RV, respectively) function. Pimobendan significantly increased LV and RV functions without increasing PAP. Conversely, dobutamine and dopamine significantly increased LV and RV function as well as PAP. This study revealed the efficacy of epoprostenol in treating canine PH through its pulmonary and systemic vasodilating effects. Although catecholamines improve LV and RV function, they might worsen PH pathophysiology, and careful monitoring may be necessary when using these drugs. Pimobendan improved LV and RV function without increasing PAP; however, a stronger vasodilating effect was observed with epoprostenol.

SGLT2 Inhibitors: Emerging Drugs in Heart Failure

Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a class of diabetes medications that have demonstrated the potential to improve outcomes for heart failure (HF) patients. Although they were originally developed to treat diabetes, clinical trials have demonstrated their ability to both reduce the risk and improve the prognosis of HF. SGLT2 inhibitors have unique mechanisms of action, including improvement of water retention and promotion of lipolysis, which contribute to their effectiveness in treating HF. They are considered essential primary treatment options for patients with HF, regardless of diabetes status and ejection fraction. Overall, the use of SGLT2 inhibitors in patients with HF is expected to increase in the future and may further improve treatment outcomes for HF patients.

Acute phosphatidylinositol 4,5 bisphosphate depletion destabilizes sarcolemmal expression of cardiac L-type Ca2+ channel CaV1.2

CaV1.2 channels are critical players in cardiac excitation-contraction coupling, yet we do not understand how they are affected by an important therapeutic target of heart failure drugs and regulator of blood pressure, angiotensin II. Signaling through Gq-coupled AT1 receptors, angiotensin II triggers a decrease in PIP2, a phosphoinositide component of the plasma membrane (PM) and known regulator of many ion channels. PIP2 depletion suppresses CaV1.2 currents in heterologous expression systems but the mechanism of this regulation and whether a similar phenomenon occurs in cardiomyocytes is unknown. Previous studies have shown that CaV1.2 currents are also suppressed by angiotensin II. We hypothesized that these two observations are linked and that PIP2 stabilizes CaV1.2 expression at the PM and angiotensin II depresses cardiac excitability by stimulating PIP2 depletion and destabilization of CaV1.2 expression. We tested this hypothesis and report that CaV1.2 channels in tsA201 cells are destabilized after AT1 receptor-triggered PIP2 depletion, leading to their dynamin-dependent endocytosis. Likewise, in cardiomyocytes, angiotensin II decreased t-tubular CaV1.2 expression and cluster size by inducing their dynamic removal from the sarcolemma. These effects were abrogated by PIP2 supplementation. Functional data revealed acute angiotensin II reduced CaV1.2 currents and Ca2+ transient amplitudes thus diminishing excitation-contraction coupling. Finally, mass spectrometry results indicated whole-heart levels of PIP2 are decreased by acute angiotensin II treatment. Based on these observations, we propose a model wherein PIP2 stabilizes CaV1.2 membrane lifetimes, and angiotensin II-induced PIP2 depletion destabilizes sarcolemmal CaV1.2, triggering their removal, and the acute reduction of CaV1.2 currents and contractility.

Association between fear of progression and sleep quality in patients with chronic heart failure: A cross-sectional study.

This study aimed to measure sleep quality and its possible association with fear of progression (FOP) in patients with chronic heart failure (HF). A cross-sectional study. A total of 254 patients with chronic HF were recruited from two tertiary hospitals in China. The sociodemographic and clinical data of participants were collected using a general information questionnaire. The Pittsburgh Sleep Quality Index and Fear of Progression Questionnaire-Short Form were used to evaluate sleep quality over 1 month and FOP. Pearson correlation and hierarchical regression were conducted to analyse the relationship between sleep quality and FOP. Of all participants, 85.8% had poor sleep quality, with a mean score of 12.3 ± 4.2 (possible score could be 0 to 21). The severity of FOP was positively correlated with poor sleep quality. HF hospitalization in the past year, numbers of HF drugs, monthly income and total score of FOP were strong predictors of decreased sleep quality, accounting for 24.2% of the variance in the sleep quality of these patients. Patients with chronic HF generally reported poor sleep quality, which should be highly concerned for medical workers. Alleviating FOP as a therapeutic strategy may improve sleep quality. It is urgent to raise clinical attention that Chinese patients with chronic HF have poor sleep quality, which is not just due to the symptoms of HF itself. FOP is an important psychological factor influencing sleep quality in patients with chronic HF, which has not been explored in China. This study provides a new perspective on targeted interventions for poor sleep quality in chronic HF. No patient or public involvement.

A high-throughput drug screening identifies luteolin as a therapeutic candidate for pathological cardiac hypertrophy and heart failure.

Pathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening. A screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin. Among 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro. Our data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.