Search Results (33)

Background/Objectives: Real-world evidence shows alarmingly suboptimal utilization of guideline directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related adverse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HFrEF (AHF) patients can be up-titrated safely and whether AHF predisposes individuals to the occurrence of putatively drug-related AEs. Methods: A total of 373 HFrEF patients with documented baseline, 2 months, and 12 months visits were analyzed for utilization and target dosages (TDs) of HF drugs. Successful up-titration and AEs were evaluated for different stages of HF reflected by N-terminal pro-B type natriuretic peptide (NT-proBNP) (<1000 pg/mL, 1000–2000 pg/mL, >2000 pg/mL). Results: A stepwise increase in HF medications was observed for all drug classes during follow-up. At 12 months, 73%, 75%, 62%, 86%, and 45% of patients received ≥90% of TDs of beta-blockers (BBs), renin–angiotensin system inhibitors (RASis), mineralocorticoid receptor antagonists (MRAs), sodium–glucose cotransporter-2 inhibitors (SGLT2 i), and triple-therapy, respectively. Predictors of successful up-titration in logistic regression were baseline HF drug TDs, estimated glomerular filtration rate (eGFR), and potassium, but not NT-proBNP or age. The development of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, the development of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases of incomplete up-titration. Conclusions: This study suggests that with dedicated protocols and frequent visits, GDMT can be successfully implemented across all stages of HFrEF, including patients with AHF. Full article

Despite the availability of several drug classes for the treatment of hypertension, the current approaches to high blood pressure (BP) are not fully satisfying the needs of this patient population. As a result, in recent years, many clinical trials have investigated novel pharmacological approaches for lowering high BP. As overactivity of the renin–angiotensin–aldosterone system is often present in hypertensive patients, especially those with resistant hypertension, several studies have focused on novel strategies to counteract this phenomenon by the use of non-steroidal inhibitors of the mineralocorticoid receptors, aldosterone synthase inhibitors or RNA-targeting therapies to inhibit the hepatic synthesis of angiotensinogen. The latter approach in particular might offer the additional advantage of reducing the daily pill burden of these patients, hence mitigating the common occurrence of non-adherence to treatment. Because obesity and diabetes are common risk factors for hypertension (a high percentage of individuals with resistant hypertension being obese), numerous investigations have analyzed the BP-lowering effects of those agents, such as glucagon-like peptide-1 receptor agonists and sodium–glucose co-transporter-2 inhibitors, which have been shown to reduce body weight and improve cardiovascular outcomes in these patients. Available evidence suggests that these drug classes can indeed afford a clinically meaningful BP decrease and, potentially, reduce the treatment burden. In conclusion, even though the rates of uncontrolled hypertension remain high, several novel therapeutic options are in the offing. As these emerging treatments will compound with many already available agents, future efforts should be directed at better phenotyping patients to tailor the most suitable approach for each one. Full article

Objectives: Randomized evidence on the role of heart failure guideline-directed medical therapy for patients with functional mitral regurgitation (FMR) is lacking. The present meta-analysis sought to investigate the prognostic impact of different pharmacotherapy categories recommended in heart failure on subjects with FMR. Methods: A systematic literature review was conducted to identify studies reporting the association of renin angiotensin system inhibitors (RASi), beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA) with outcomes in FMR. A random-effects meta-analysis was conducted to quantify the unadjusted and adjusted hazard ratios [(a)HRs] for all-cause death and the composite outcome in each medical category. Results: Twelve studies with 6,715 FMR patients were included. The use of RASi and BB was associated with a significantly lower risk of all-cause mortality (HR 0.52 [0.39–0.68]; p < 0.00001, I² = 62% and HR 0.62 [0.49–0.77]; p < 0.0001, I² = 44%, respectively) and the composite outcome (HR 0.54 [0.44–0.67]; p < 0.00001, I² = 33% and HR 0.62 [0.52–0.75], p < 0.00001, I² = 35%, respectively) in unadjusted models. Both RASi (aHR 0.73 [0.56–0.95], p = 0.02, I² = 52%) and BB (aHR 0.60 [0.41–0.88], p = 0.009, I² = 55%) retained their association with the composite outcome in pooled adjusted models. The prognostic benefit of using RASi or BB was retained in subgroup analyses including only (1) patients with moderate or severe FMR and (2) patients with reduced or mildly reduced left ventricular ejection fraction. MRA did not demonstrate a significant association with improved outcomes. Conclusions: RASi and BB administration appear to have a favorable prognostic impact on patients with FMR, regardless of the severity of regurgitation. Full article

In heart failure (HF) patients undergoing cardiac surgery, an increased activity of mechanisms related to cardiac remodeling may determine a higher risk of postoperative atrial fibrillation (POAF). Given that atrial fibrillation (AF) has a negative impact on the course and management of HF, including the need for anticoagulation therapy, identifying the factors associated with AF occurrence after cardiac surgery is crucial for the prognosis of these patients. POAF is thought to occur when various clinical and biochemical triggers act on susceptible cardiac tissue (first hit), with oxidative stress and inflammation during cardiopulmonary bypass (CPB) surgery being potential contributing factors (second hit). However, the molecular mechanisms involved in these processes remain poorly characterized. Recent research has shown that patients who later develop POAF often have pre-existing abnormalities in calcium handling and activation of NLRP3-inflammasome signaling in their atrial cardiomyocytes. These molecular changes may make cardiomyocytes more susceptible to spontaneous Ca2+-releases and subsequent arrhythmias, particularly when exposed to inflammatory mediators. Additionally, some clinical studies have linked POAF with elevated preoperative inflammatory markers, but there is a need for further research in order to better understand the impact of CPB surgery on local and systemic inflammation. This knowledge would make it possible to determine whether patients susceptible to POAF have pre-existing inflammatory conditions or cellular electrophysiological factors that make them more prone to developing AF and cardiac remodeling. In this context, the NLRP3 inflammasome, expressed in cardiomyocytes and cardiac fibroblasts, has been identified as playing a key role in the development of HF and AF, making patients with pre-existing HF with reduced ejection fraction (HFrEF) the focus of several clinical studies with interventions that act at this level. On the other hand, HFpEF has been linked to metabolic and non-ischemic risk factors, but more research is needed to better characterize the myocardial remodeling events associated with HFpEF. Therefore, since ventricular remodeling may differ between HFrEF and HFpEF, it is necessary to perform studies in both groups of patients due to their pathophysiological variations. Clinical evidence has shown that pharmacological therapies that are effective for HFrEF may not provide the same anti-remodeling benefits in HFpEF patients, particularly compared to traditional adrenergic and renin–angiotensin–aldosterone system inhibitors. On the other hand, there is growing interest in medications with pleiotropic or antioxidant/anti-inflammatory effects, such as sodium–glucose cotransporter 2 inhibitors (SGLT-2is). These drugs may offer anti-remodeling effects in both HFrEF and HFpEF by inhibiting pro-inflammatory, pro-oxidant, and NLRP3 signaling pathways and their mediators. The anti-inflammatory, antioxidant, and anti-remodeling effects of SGLT-2 i have progressively expanded from HFrEF and HFpEF to other forms of cardiac remodeling. However, these advances in research have not yet encompassed POAF despite its associations with inflammation, oxidative stress, and remodeling. Currently, the direct or indirect effects of NLRP3-dependent pathway inhibition on the occurrence of POAF have not been clinically assessed. However, given that NLRP3 pathway inhibition may also indirectly affect other pathways, such as inhibition of NF-kappaB or inhibition of matrix synthesis, which are strongly linked to POAF and cardiac remodeling, it is reasonable to hypothesize that this type of intervention could play a role in preventing these events. Full article

The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease. In the kidney, endothelins are produced in mesangial cells and the glomerular basement membrane by the endothelium and podocytes. The endothelin system regulates glomerular function by inducing proliferation, increasing permeability and in effect proteinuria, and stimulating inflammation, tubular fibrosis, and glomerular scarring. Endothelin A receptor antagonists have been proven to delay the progression of chronic kidney disease and play a protective role in immunoglobulin A nephropathy, focal segmental glomerulosclerosis, and diabetic nephropathy. There are several ongoing research studies with ETAR antagonists in nondiabetic nephropathy, Alport disease, vasculitis and scleroderma nephropathy, which results are promising. Some reports suggest that the endothelin system might contribute to ischemia–reperfusion injury, acute graft rejection and deterioration of graft function. Endothelin inhibition in renal transplantation and its influence on graft survival is the future direction needing further research. The most frequent side effects associated with ETAR antagonists is fluid retention. Additionally, it should be considered if selective ETAR antagonists therapy needs to be co-administered with sodium-glucose co-transporter 2 inhibitors, renin–angiotensin–aldosterone inhibitors or diuretics and which patients should be recruited to such treatment to minimize the risk of adverse outcomes. Full article

Human serum albumin (HSA) is an endogenous inhibitor of angiotensin I-converting enzyme (ACE) and, thus, plays a key role in the renin–angiotensin–aldosterone system (RAAS). However, little is known about the mechanism of interaction between these proteins, and the structure of the HSA–ACE complex has not yet been obtained experimentally. The purpose of the presented work is to apply computer modeling methods to study the interaction of HSA with ACE in order to obtain preliminary details about the mechanism of their interaction. Ten possible HSA–ACE complexes were obtained by the procedure of macromolecular docking. Based on the number of steric and polar contacts between the proteins, three leading complexes were selected, the stabilities of which were then tested by molecular dynamics (MD) simulation. Based on the results of MD simulation, the two most probable conformations of the HSA–ACE complex were selected. The analysis of these conformations revealed that the processes of oxidation of the thiol group of Cys34 of HSA and the binding of albumin to ACE can reciprocally affect each other. Known point mutations in the albumin molecules Glu82Lys, Arg114Gly, Glu505Lys, Glu565Lys and Lys573Glu can also affect the interaction with ACE. According to the result of MD simulation, the known ACE mutations, albeit associated with various diseases, do not affect the HSA–ACE interaction. A comparative analysis was performed of the resulting HSA–ACE complexes with those obtained by AlphaFold 3 as well as with the crystal structure of the HSA and the neonatal Fc receptor (FcRn) complex. It was found that domains DI and DIII of albumin are involved in binding both ACE and FcRn. The obtained results of molecular modeling outline the direction for further study of the mechanisms of HSA–ACE interaction in vitro. Information about these mechanisms will help in the design and improvement of pharmacotherapy aimed at modulation of the physiological activity of ACE. Full article

Cardiorenal syndrome (CRS) is a life-threatening disorder that involves a complex interplay between the two organs. Managing this multifaceted syndrome is challenging in the hospital and requires a multidisciplinary approach to tackle the many manifestations and complications. There is no universally accepted algorithm to treat patients, and therapeutic options vary from one patient to another. The mainstays of therapy involve the stabilization of hemodynamics, decongestion using diuretics or renal replacement therapy, improvement of cardiac output with inotropes, and goal-directed medical treatment with renin–angiotensin–aldosterone system inhibitors, beta-blockers, and other medications. Mechanical circulatory support is another viable option in the armamentarium of agents that improve symptoms in select patients. Full article

Purpose: Acute heart failure (AHF) is associated with high morbidity and mortality, and the prognosis is particularly poor in older patients. Although the application of guideline-directed medical therapy (GDMT) has shown a positive impact on prognosis, the effects are less clear in older age groups. The aim of this study was to analyze real-world data regarding GDMT and outcomes in older HF patients. Methods: This is a prospective cohort study from a secondary care hospital in central Switzerland. A total of 97 consecutive patients aged ≥60 years were enrolled between January 2019 and 2022. The main outcome parameters were prescribed GDMT at discharge, and in case of rehospitalization, GDMT at readmission, and survival in terms of all-cause mortality and HF-related hospitalizations during a 3-year follow-up period. Results: Follow-up data were available for 93/97 patients. The mean age was 77.8 ± 9.8 years, 46% being female. The mean left ventricular ejection fraction (LVEF) was 35.3 ± 13.9%, with a mean BNP level of 2204.3 ± 239 ng/L. Upon discharge, 86% received beta-blockers and 76.3% received renin–angiotensin system (RAS) inhibitors. At rehospitalization for AHF, beta-blockers use was significantly lower and decreased to 52.8% (p = 0.003), whereas RAS inhibitor use increased slightly to 88.9% (p = 0.07), and SGLT-2 inhibitors showed a significant increase from 5.4% vs. 47.2% (p = 0.04). GDMT prescription was not dependent on LVEF. Overall, 73.1% of patients received two-stage or three-stage GDMT at discharge, whereas this percentage decreased to 61% at rehospitalization (p = 0.01). Kaplan–Meier analysis for the combined outcome rehospitalization and death stratified by LV function showed significant differences between LVEF groups (aHR: 0.6 [95% CI: 0.44 to 0.8]; p = 0.0023). Conclusions: Our results indicate that first, the majority of older AHF patients from a secondary care hospital in Switzerland were not on optimal GDMT at discharge and even fewer at readmission, and second, that prognosis of the population is still poor, with almost half of the patients having been rehospitalized or died during a 3-year follow-up period under real-world conditions, without significant difference between women and men. Our findings underline the need for further improvements in the medical treatment of AHF, in particular in older patients, to improve prognosis and to reduce the burden of disease. Full article

Sudden cardiac death (SCD) accounts for a substantial proportion of mortality in heart failure with reduced ejection fraction (HFrEF), frequently triggered by ventricular arrhythmias (VA). This review aims to analyze the pathophysiological mechanisms underlying VA and SCD in HFrEF and evaluate the effectiveness of guideline-directed medical therapy (GDMT) in reducing SCD. Beta-blockers, angiotensin receptor–neprilysin inhibitors, and mineralocorticoid receptor antagonists have shown significant efficacy in reducing SCD risk. While angiotensin-converting enzyme inhibitors and angiotensin receptor blockers exert beneficial impacts on the renin-angiotensin-aldosterone system, their direct role in SCD prevention remains less clear. Emerging treatments like sodium-glucose cotransporter 2 inhibitors show promise but necessitate further research for conclusive evidence. The favorable outcomes of those molecules on VA are notably attributable to sympathetic nervous system modulation, structural remodeling attenuation, and ion channel stabilization. A multidimensional pharmacological approach targeting those pathophysiological mechanisms offers a complete and synergy approach to reducing SCD risk, thereby highlighting the importance of optimizing GDMT for HFrEF. The current landscape of HFrEF pharmacotherapy is evolving, with ongoing research needed to clarify the full extent of the anti-arrhythmic benefits offered by both existing and new treatments. Full article

Developing effective anti-fibrotic therapies for heart diseases holds the potential to address unmet needs in several cardiac conditions, including heart failure with preserved ejection fraction, hypertrophic cardiomyopathy, and cardiotoxicity induced by cancer therapy. The inhibition of the primary fibrotic regulator, transforming growth factor (TGF) β, represents an efficient strategy for mitigating fibrosis in preclinical models. However, translating these findings into clinical benefits faces challenges due to potential adverse effects stemming from TGF-β’s physiological actions in inflammation and tissue homeostasis. Various strategies exist for inhibiting TGF-β, each associated with a distinct risk of adverse effects. Targeting TGF-β directly or through its signaling pathway proves efficient in reducing fibrosis. However, direct TGF-β blockade may lead to uncontrolled inflammation, especially following myocardial infarction, while interference with the signaling pathway may compromise structural integrity, resulting in issues like insufficient wound healing or ventricular dilatation. Influencing TGF-β activity through interacting signaling pathways, for instance by inhibitors of the renin–angiotensin–aldosterone-system, is insufficiently potent in reducing fibrosis. Targeting activators of latent TGF-β, including ADAMTS enzymes, thrombospondin, and integrins, emerges as a potentially safer strategy to reduce TGF-β-induced fibrosis but it requires the identification of appropriate targets. Encouragement is drawn from promising agents developed for fibrosis in other organs, fueling hope for similar breakthroughs in treating cardiac fibrosis. Such advances depend on overcoming obstacles for the implementation of anti-fibrotic strategies in patients with heart disease, including fibrosis quantification. In this review, insights garnered from interventional and mechanistic studies, obtained through a non-systemic search spanning preclinical and clinical evidence, are summarized to pinpoint the most promising targets for further exploration and development. Full article

We aimed to determine effects of aliskiren, a direct renin inhibitor, loaded onto polymeric nanoparticles on the (pro)renin receptor (Atp6ap2), angiotensin II type 1 receptor (Agtr1), and angiotensin-converting enzyme (ACE) gene expression in the heart of spontaneously hypertensive rats (SHR). Twelve-week-old male SHRs were divided into an untreated group and groups treated with powdered aliskiren or aliskiren-loaded nanoparticles (25 mg/kg/day). After three weeks, the accumulation of aliskiren, distribution of polymeric nanoparticles, gene expression of Atp6ap2 and Agtr1 receptors and ACE, and protein expression of NADPH oxidase along with the conjugated diene (CD) concentration were analyzed. The accumulation of aliskiren in the heart was higher in the aliskiren-loaded nanoparticle group than in the powdered group. The fluorescent signals of nanoparticles were visible in cardiomyocytes, vessel walls, and erythrocytes. Aliskiren-loaded nanoparticles decreased the gene expression of Atp6ap2 and ACE, while not affecting Agtr1. Both forms of aliskiren decreased the protein expression of NADPH oxidase, with a more pronounced effect observed in the aliskiren-loaded nanoparticle group. CD concentration was decreased only in the aliskiren-loaded nanoparticle group. We hypothesize that aliskiren-loaded nanoparticle-mediated downregulation of Atp6ap2 and ACE may contribute to a decrease in ROS generation with beneficial effects in the heart. Moreover, polymeric nanoparticles may represent a promising tool for targeted delivery of aliskiren. Full article

In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin–angiotensin–aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems (neurohumoral antagonists) and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated. Full article

Hypertension is the third leading cause of the global disease burden, and while populations live longer, adopt more sedentary lifestyles, and become less economically concerned, the prevalence of hypertension is expected to increase. Pathologically elevated blood pressure (BP) is the strongest risk factor for cardiovascular disease (CVD) and related disability, thus making it imperative to treat this disease. Effective standard pharmacological treatments, i.e., diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blocker (ARBs), beta-adrenergic receptor blockers (BARBs), and calcium channel blockers (CCBs), are available. Vitamin D (vitD) is known best for its role in bone and mineral homeostasis. Studies with vitamin D receptor (VDR) knockout mice show an increased renin–angiotensin–aldosterone system (RAAS) activity and increased hypertension, suggesting a key role for vitD as a potential antihypertensive agent. Similar studies in humans displayed ambiguous and mixed results. No direct antihypertensive effect was shown, nor a significant impact on the human RAAS. Interestingly, human studies supplementing vitD with other antihypertensive agents reported more promising results. VitD is considered a safe supplement, proposing its great potential as antihypertensive supplement. The aim of this review is to examine the current knowledge about vitD and its role in the treatment of hypertension. Full article

Stress is an organism’s response to a biological or psychological stressor, a method of responding to threats. The autonomic nervous system and hypothalamic–pituitary–adrenal axis (HPA axis) regulate adaptation to acute stress and secrete hormones and excitatory amino acids. This process can induce excessive inflammatory reactions to the central nervous system (CNS) by HPA axis, glutamate, renin-angiotensin system (RAS) etc., under persistent stress conditions, resulting in neuroinflammation. Therefore, in order to treat stress-related neuroinflammation, the improvement effects of several mechanisms of receptor antagonist and pharmacological anti-inflammation treatment were studied. The N-methyl-D-aspartate (NMDA) receptor antagonist, peroxisome proliferator-activated receptor agonist, angiotensin-converting enzyme inhibitor etc., effectively improved neuroinflammation. The interesting fact is that not only can direct anti-inflammation treatment improve neuroinflammation, but so can stress reduction or pharmacological antidepressants. The antidepressant treatments, including selective serotonin reuptake inhibitors (SSRI), also helped improve stress-related neuroinflammation. It presents the direction of future development of stress-related neuroinflammation drugs. Therefore, in this review, the mechanism of stress-related neuroinflammation and pharmacological treatment candidates for it were reviewed. In addition, treatment candidates that have not yet been verified but indicate possibilities were also reviewed. Full article

Symptomatic heart failure with reduced ejection fraction (HFrEF) is characterized by edema and chronic pathological activation of the classical renin–angiotensin–aldosterone system (RAAS). The soluble (pro)renin receptor (s(P)RR) is released into circulation by proteolytic cleavage of tissue expressed (P)RR and is a candidate biomarker of RAAS activation. However, previous studies linked elevated levels of s(P)RR in patients with HFrEF to renal dysfunction. Utilizing prospectively enrolled patients with comparable rEF, we show that increased plasma levels of s(P)RR are associated with symptomatic HF (characterized by edema), independent of chronic renal dysfunction. We also found that s(P)RR levels were positively correlated with patient plasma renin activity (PRA). Normotensive mice with dilated cardiomyopathy (DCM) and HFrEF, without renal dysfunction, showed plasma s(P)RR and PRA patterns similar to human HFrEF patients. Plasma s(P)RR levels positively correlated with PRA and systemic edema, but not with EF, resembling findings in patients with HFrEF without chronic kidney dysfunction. In female DCM mice with elevated PRA levels and plasma s(P)RR levels, a randomized, blinded trial comparing the direct renin inhibitor, aliskiren vs. vehicle control, showed that direct renin inhibition normalized PRA, lowered s(P)RR, and prevented symptomatic HFrEF. Considered in light of previous findings, these data suggest that, in HFrEF, in the absence of renal dysfunction, elevation of plasma s(P)RR levels is caused by increased PRA and associated with the development of systemic edema. Full article