Search Results (126)

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

Background/Objectives: Pulmonary hypertension (PH) is a progressive disorder with high morbidity and mortality, partly driven by chronic inflammation. Soluble urokinase plasminogen activator receptor (suPAR) reflects immune activation. We evaluated whether suPAR is altered in Group 1 and Group 4 PH and its association with clinical, echocardiographic, and laboratory parameters. Methods: We enrolled 44 PH patients (36 in Group 1, 8 in Group 4) and 45 healthy controls. All underwent clinical and echocardiographic assessments; right heart catheterization was performed in the PH patients. Serum suPAR was measured by ELISA. N-terminal pro B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) were also assessed. Results: The suPAR plasma levels in the PH group were between 23.91 and 960.8 pg/mL (median: 73.14 p25: 62.77, p75: 167.13). suPAR was significantly higher in PH versus controls (73.14 [62.77–167.13] vs. 65.52 [53.06–80.91] pg/mL; p = 0.012). In logistic regression, systolic blood pressure, erythrocyte sedimentation rate, NT-proBNP, and suPAR independently predicted PH. suPAR correlated negatively with six-minute walk distance (r = −0.310) and tricuspid annular plane systolic excursion (r = −0.295) but positively with systolic pulmonary artery pressure (r = 0.241). On multivariate analysis, six-minute walk distance was the only independent correlate of suPAR (p = 0.004). suPAR levels did not differ between Group 1 and Group 4 PH. Conclusions: suPAR is elevated in Group 1 and Group 4 PH and correlates with functional and echocardiographic indices of disease severity. Larger prospective studies are needed to determine suPAR’s role in diagnosis, risk stratification, and therapeutic decision-making. Full article

Brugada syndrome (BrS) is a cardiac disease associated with characteristic ECG abnormalities and a heightened risk of sudden cardiac death, especially in young individuals with structurally normal hearts. The primary aim of this study was to highlight, for the first time, the potential of using droplet digital PCR (ddPCR), a highly sensitive method, to detect C-type natriuretic peptide (CNP) and its receptors, NPR-B and NPR-C, expression in BrS. Whole-blood samples from 12 subjects with type 1 BrS and 12 controls were analyzed. CNP expression was detectable and lower in BrS patients than in the controls, although not significantly. NPR-B and NPR-C expression was significantly reduced in the same patients (p ≤ 0.05). Strong correlations were observed between CNP and NPR-B (p = 0.01) and NPR-C (p < 0.0001), as well as between NPR-B and NPR-C (p = 0.0002). Body weight correlated with CNP (p = 0.02), NPR-B (p = 0.03), and NPR-C (p = 0.02); meanwhile, NPR-B expression was related to height (p = 0.05). This study is the first to analyze CNP expression and its specific receptors using ddPCR technology, showing for the first time their presence and activation in individuals with BrS. Although further research is needed to clarify CNP-related mechanisms, these findings offer a valuable starting point for exploring its role in BrS. Full article

Background/Objectives: Heart failure (HF) with preserved ejection fraction (HFpEF) poses a diagnostic challenge, as it lacks a definitive hallmark beyond preserved left ventricular (LV)EF. This retrospective study aims to analyze the demographic and clinical characteristics of HFpEF patients within a real-world hospital cohort, with a particular focus on obesity and associated comorbidities. Methods: A total of 4019 patients who underwent echocardiography in 2020–2021 at a university hospital were screened for HFpEF. After stringent manual verification, 219 patients fulfilled the European Society of Cardiology (ESC) criteria for HFpEF. Demographic, clinical, and comorbidity data were analyzed and stratified by body mass index (BMI) categories and sex distribution. Results: Among the 219 HFpEF patients, 71.3% were classified as pre-obese or obese. Hypertension (93.6%), atrial fibrillation (74.3%), and obesity were common in the cohort, while sex distribution was balanced. Edema was more prevalent among obese patients, though HFpEF severity, as reflected by New York Heart Association (NYHA) classification and natriuretic peptide levels, did not differ significantly across BMI groups. Medical treatment patterns varied with BMI, with obese patients more frequently receiving diuretics, sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and angiotensin receptor blockers (ARB). No significant differences were observed between male and female patients in terms of HFpEF severity markers. Conclusions: Obesity is a predominant feature in HFpEF and is associated with a high burden of comorbidities. However, sex does not appear to influence HFpEF severity in this cohort. These findings underscore the need for targeted therapeutic strategies in obese HFpEF patients. Full article

Physiological control of blood pressure (BP) and extracellular fluid volume is mediated by the action of the renin-angiotensin system (RAS). The presence of RAS components throughout the nephron has been widely discussed. The (pro)renin receptor (PRR) is a member of the RAS widely expressed in the body of humans and rodents. In the kidney, PRR is expressed in mesangial cells, renal vasculature, and tubules of the proximal and distal nephron. Binding of the PRR to renin and prorenin promotes angiotensin (Ang) I-mediated sodium (Na⁺) reabsorption via the epithelial sodium channel (ENaC). The Goldblatt 2-kidney 1-clip (2K1C) is a model of experimental renovascular hypertension that displays activation of systemic and intrarenal RAS. We use the 2K1C hypertension mouse model for 7 days to evaluate the role of the PRR on renal αENaC expression, Na⁺ reabsorption, and BP using pharmacological systemic blockade of the PRR with PRO20 peptide. Mice undergoing or not to 2K1C surgery (0.13 mm clip internal gap) were chronically infused with PRO20 and compared to sham (control) mice to assess changes in systolic BP (SBP) and diastolic BP (DBP), intrarenal angiotensin-converting enzyme (ACE) activity, Ang II, and renal αENaC expression and natriuretic responses after a saline challenge. Renal artery obstruction increased SBP and DBP, intrarenal ACE activity, Ang II levels, Na⁺ retention, and αENaC expression in both kidneys. PRO20 prevented the increases in SBP, DBP, attenuated Na⁺ retention, and blunted intrarenal Ang II and αENaC levels in non-clipped kidneys of 2K1C mice. Chronic infusion of the PRR for 7 days prevents hypertensive responses in part due to impaired αENaC upregulation and intrarenal Ang II formation in the early phase of the development of renovascular hypertension in 2K1C Goldblatt mice. Full article

Systemic sclerosis, a connective tissue disease of unknown etiology and unpredictable outcomes, is characterized by the fibrosis of the skin and internal organs, vasculopathy, and immune system dysregulation. The disease is classified into two main subtypes, which differ in clinical presentation, complications, and prognosis. While several biomarkers have been proposed to distinguish between these subtypes, none have achieved high sensitivity and specificity. The search for dependable markers that can differentiate between the two primary subtypes of systemic sclerosis continues. To address this gap, our study evaluated the utility of novel cardiac biomarkers, including growth differentiation factor 15 (GDF15), galectin-3, mid-regional pro-atrial natriuretic peptide (MR-proANP), glutathione S-transferase π, mid-regional adrenomedullin, and soluble urokinase plasminogen activator receptor (suPAR), in a cohort of 79 patients with both lcSSc and dSSc subtypes. The results demonstrated a significant elevation of GDF15 (medians: 2.07 vs. 1.10 ng/L; p < 0.001) and MR-proANP (92.55 vs. 65.60 pmol/L; p < 0.05) levels in SSc patients compared to healthy controls. Moreover, GDF15 (1.65 vs. 2.34 ng/mL; p < 0.05), MR-proANP (80.87 vs. 109.27 pmol/L; p < 0.05), and suPAR (1.83 vs. 2.44 ng/mL; p < 0.05) levels were notably higher in patients with dSSc compared to those with lcSSc. In the ROC analysis, only GDF-15, MR-proANP, and suPAR proved to have a statistically significant area under the curve (AUC). Patients with the GDF-15 ≥ 2182 ng/mL, MR-prANP ≥ 85.808 pmol/L, and suPAR ≥ 2.315 ng/mL have more than six-, eight-, and seven-times-higher odds for dcSSc, respectively. These findings highlight the potential of GDF15, suPAR, and MR-proANP as biomarkers for differentiating between the two main subtypes of systemic sclerosis. Full article

Background: Suppression of Tumorigenicity 2 (ST2), a member of the interleukin-1 receptor family, plays a crucial role in immune regulation. Elevated sST2 levels are associated with poor prognosis in various inflammatory and cardiovascular diseases, including acute heart failure (AHF), sepsis and transplant rejection. Objectives and methods: This study aimed to evaluate the diagnostic and prognostic accuracy of sST2, along with other biomarkers, such as high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), procalcitonin (PCT) and mid-regional pro-adrenomedullin (MR-proADM), in patients with AHF, sepsis and AHF/sepsis overlap. Results: A cohort of 74 patients was analyzed, and comparison statistics revealed that sST2 levels were significantly higher in the AHF/sepsis group (113.88 ng/mL) compared to the AHF group (42.24 ng/mL, p = 0.024), while no significant difference was observed between sepsis and AHF groups (p = 0.10). Other biomarkers, including hs-CRP and PCT, showed significant differences between the AHF and AHF/sepsis groups. ROC curve analysis identified sST2 as a strong predictor of mortality and readmission, with high AUC values for 30-day readmission (0.821) and mortality (0.87). Conclusions: These findings suggest that combining biomarkers, including sST2, could improve the early diagnosis, risk stratification and management of critically ill patients with overlapping AHF and sepsis. Further studies with larger populations are needed to validate these findings and explore the potential of integrating these biomarkers into clinical practice. Full article

Heart failure (HF) is a challenging clinical syndrome with high morbidity and mortality rates. Along the spectrum of cardiovascular diseases, HF constitutes an ever-expanding area of research aiming at combating the associated mortality and improving the prognosis of patients with HF. Although natriuretic peptides have an established role among biomarkers in HF diagnosis and prognosis, several novel biomarkers reflecting the complex pathophysiology of HF are under investigation for their ability to predict adverse clinical outcomes in HF. Proenkephalin 119–159 (PENK_119–159) is a non-functional peptide belonging to the enkephalin family of the endogenous opioid system and is considered a surrogate biomarker of the biologically active enkephalin peptides. PENK_119–159 has demonstrated promising results in predicting short- and long-term mortality, readmission rates, and worsening renal function in patients with HF. Indeed, in the setting of HF, the levels of both active enkephalins and their surrogate PENK_119–159 are elevated and are associated with a dismal prognosis. However, the biological effects of PENK_119–159 remain largely unknown. Thus, it is crucial to gain a deeper insight into both the physiology of the enkephalin peptide family and the enkephalin-mediated cardiovascular regulation. In order to elucidate the complex pathophysiological mechanisms that lead to the upregulation of enkephalins in patients with HF, as well as the potential clinical implications of elevated enkephalins and PENK_119–159 levels in this patient population, the present review will describe the physiology and distribution of the endogenous opioid peptides and their corresponding opioid receptors, with a particular focus on the action of enkephalins. The effects of the enkephalin peptides will be analyzed in both healthy subjects and patients with HF, especially with regard to their role in the regulation of cardiovascular and renal function. The review will also discuss the findings of recent studies that have explored the prognostic value of PENK_119–159 in patients with HF. Full article

Background/Objectives: Heart transplantation (HTX) is the definitive treatment for advanced heart failure (AdHF). The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (S/V) has been shown to reduce heart failure (HF) hospitalizations and mortality when compared to conventionally administered HF medications (i.e. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)). Nevertheless, limited data are available on the hemodynamic (HD) effects of ARNI in patients with AdHF. Therefore, the aim of the present study was to compare echocardiographic, laboratory, and HD parameters relevant to HF before and after switching to ARNI in patients with AdHF awaiting HTX. Methods: A retrospective analysis was conducted utilizing available data on HD parameters, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, data on kidney function, HF therapy, and comorbidities. The study cohort comprised 13 AdHF patients (3 women, 10 men; mean age 56.4 ± 9 years) of whom 53.8% presented with non-ischemic and 46.2% with ischemic etiology. All patients were awaiting heart transplantation (HTX) and were transitioned to ARNI therapy between 2018 and 2021. Results: After switching to ARNI, we observed significant improvements: in left ventricular ejection fraction (LVEF: 27.27 ± 1.04% vs. 23.65 ± 1.02%, p = 0.03; data are given as mean ± SEM after vs. before ARNI therapy, respectively), cardiac output (CO: 4.90 ± 0.35 L/min vs. 3.83 ± 0.24 L/min, p = 0.013), and stroke volume (SV: 70.9 ± 5.9 mL vs. 55.5 ± 4.12 mL, p = 0.013). Significant reductions in systemic vascular resistance (SVR: 1188 ± 79.8 vs. 1600 ± 100 DS/cm⁵, p = 0.004) and pulmonary vascular resistance (PVR: 232.5 ± 34.8 vs. 278.9 ± 31.7 DS/cm⁵, p = 0.04) were also noted. Central venous pressure (CVP), pulmonary arterial systolic and diastolic pressures (PAPs and PAPd), pulmonary capillary wedge pressure (PCWP), and NT-proBNP levels did not exhibit significant changes upon ARNI administration. Conclusions: Early transition to ARNI therapy offers significant benefits for invasively measured hemodynamic parameters in patients with AdHF, potentially aiding in the stabilization and improvement of this vulnerable patient population. Full article

(1) Pediatric inflammatory multisystem syndrome (PIMS) is a relatively rare complication of coronavirus disease (COVID-19). So far, it is unclear why COVID-19 in children has usually mild or asymptomatic courses, whereas PIMS, which develops several weeks after COVID-19, is a serious life-threatening condition. (2) In this proof-of-concept study, using the ELISA method, we compared selected clinical and immunological parameters in small groups of children with PIMS and COVID-19. Children with various inflammatory diseases were included as a control. (3) Patients with PIMS revealed significantly higher levels of pro-inflammatory molecules (C-reactive protein and IL-6) and markers of heart injury (troponin I and N-terminal prohormone of brain natriuretic peptide) as compared to other groups. Moreover, these markers correlated with increased levels of soluble receptors for tumor necrosis factor (sTNF-R1 and sTNF-R2). (4) Our observation may be a step forward to better understand the phenomenon of mild COVID-19 in children and its severe complications in PIMS. It is hypothesized that the delayed inflammation results in excessive cardiomyocyte damage and the release of sTNF-R1 and -R2. Therefore, possibly the involvement of the TNF pathway in PIMS could be explored as a potential therapeutic target. However, further studies are required to validate this approach. Full article

A healthy lifestyle plays a key role for maintaining the cardiovascular health (CVH) status and prevent cardiovascular disease occurrence. In fact, a healthy lifestyle was included in the AHA Cardiovascular Health score (Life’s Simple 7 [LS7]), subsequently updated to Life’s Simple 8 [LS8]. Apart from the importance of controlling conventional cardiovascular risk factors, increasing evidence supports the contributory role of cardiovascular hormones. Higher levels of natriuretic peptides (NPs) and lower levels of renin and aldosterone were significantly associated to CVH. NT-proBNP levels showed a direct relationship with CVH scores in large general Caucasian populations, being also a marker of CVH changes and a predictor of future adverse events. On the other hand, renin and aldosterone were inversely related to CVH scores. In contrast, the counter-regulatory angiotensins [Ang (1-7) acting through Mas receptor, Ang (1-9) acting through Angiotensin Type 2 receptor, and alamandine] strengthen the beneficial properties of NPs. This evidence can be explained by both the effects on systemic hemodynamic and possible pleiotropic local functions regulating different pathways involved in the maintenance of CVH. Based on the current evidence, circulating levels of NT-proBNP, renin and aldosterone may affect CVH in apparently asymptomatic individuals and represent additional markers of residual cardiovascular risk. Full article

Vascular smooth muscle cell (SMC) relaxation by guanylyl cyclases (GCs) and cGMP is mediated by NO and its receptor soluble GC (sGC) or natriuretic peptides (NPs) ANP/BNP and CNP with the receptors GC-A and GC-B, respectively. It is commonly accepted that cultured SMCs differ from those in intact vessels. Nevertheless, cell culture often remains the first step for signaling investigations and drug testing. Previously, we showed that even popular reference genes changed dramatically after SMC isolation from aorta. Regarding NP receptors, a substantial amount of data relies on cell culture. We hypothesize that the NP/cGMP system in intact aortic tunica media differs from isolated and cultured aortic SMCs. Therefore, we studied isolation and culturing effects on the expression of NP receptors GC-A, GC-B, and NP clearance receptor (NPRC) compared to sGC. We investigated intact tunica media and primary SMCs from the longitudinal halves of the same rat aorta. GC activity was monitored by cyclic guanosine monophosphate (cGMP). In addition, we hypothesize that there are sex-dependent differences in the NP/cGMP cascade in both intact tissue and cultured cells. We, therefore, analyzed a male and female cohort. Expression was quantified by RT-qPCR comparing aortic media and SMCs with our recently validated reference gene (RG) small nuclear ribonucleoprotein 2 (U2). Only GC-A was stably expressed. In intact media, GC-A exceeded GC-B and NPRC. However, GC-B, NPRC, and sGC were dramatically upregulated in cultured SMCs of the same aortae different from the stable GC-A. The expression was mirrored by NP-induced GC activity. In cultured cells, changes in GC activity were delayed compared to receptor expression. Minor differences between both sexes could also be revealed. Thus, isolation and culture fundamentally alter the cGMP system in vascular SMCs with potential impact on drug testing and scRNAseq. Especially, the dramatic increase in the clearance receptor NPRC in culture might distort all physiological ANP, BNP, and CNP effects. Full article

Growth hormone (GH) signaling is essential for heart development. Both GH deficiency and excess raise cardiovascular risk. Human (h) and mouse (m) GH differ structurally and functionally: hGH binds both the GH receptor (GHR) and prolactin receptor (PRLR), whereas mGH binds only GHR; thus, there is the potential for differential effects. We generated transgenic (hGH-TG) mice that produce pituitary hGH in response to hypothalamic signaling. These mice grow at the same rate as mGH-expressing wild-type (mGH-WT) mice but are smaller and have higher body fat. Echocardiography was used here to compare hGH-TG and mGH-WT mouse hearts. Male hGH-TG mice show a 48% lower left ventricular mass, 36% lower stroke volume, and 48% reduced cardiac output, resembling GH deficiency. Diastolic dysfunction, restrictive ventricular filling, and lower heart rate are suggested in hGH-TG mice. No significant differences in ejection fraction or fractional shortening were observed, even after high-fat diet (HFD) stress. HFD did not affect RNA markers of cardiac damage, although a possible association between B-type natriuretic peptide RNA levels and heart rate was detected. These observations suggest that diastolic dysfunction related to hGH and/or low GH might be offset by a lower heart rate, while structural changes precede functional effects. Full article

Introduction: Sacubitril/valsartan is an angiotensin receptor–neprilysin inhibitor (ARNI) drug used to treat patients with heart failure and has shown improvement in outcomes. Different studies reported the use of an ARNI in patients using left ventricular assist devices (LVADs). However, there are limited data on the use of ARNIs in this population. We aimed to assess the efficacy of ARNIs in LVAD patients. Methods: A systematic search was performed in PubMed, Scopus, Web of Science, Embase, and Cochrane from inception to November 2024. We used all relevant words for “ARNI” and “LVAD” to search, and we included studies that assessed ARNIs in patients with LVAD. Efficacy and safety outcomes were extracted from the included studies. R software version 4.4.2 was used for a meta-analysis. Results: Seven studies totaling 249 patients were included. The ARNI was found to be effective in improvements from baseline in the New York Heart Association (NYHA), B-type natriuretic peptide (BNP) (mean = −630.07 pg/mL, 95% CI [−1113.13, −147.01]), diuretic dose (furosemide equivalents) (mean= −76.05 mg/day, 95% CI [−145.11, −6.99]), left ventricular end-diastolic diameter (LVEED) (mean = −7.3 mm, 95% CI [−11.4, −3.1]), and left ventricular ejection fraction (LVEF) (mean =5, 95% CI [3.52, 6.48]). No improvement was found in the creatinine (Cr) level. However, a slight increase in the potassium level was noticed (mean= 0.17 mEq/L, 95% CI [0.02, 0.34]). The overall mortality in patients using the ARNI was 5%, 95% CI [0.00, 20], and discontinuation was found in 25%, 95% CI [0, 100]. Conclusions: The ARNI improved several cardiac structural and hemodynamic parameters in patients on LVAD support. Full article

Background: Even in current guideline-directed medical therapy, including recently introduced vasopressin type 2 receptor antagonist tolvaptan, congestion has not been resolved in patients with heart failure. Kampo medicine goreisan has been receiving considerable attention as an additional therapy for patients who are refractory to conventional diuretics therapy, including tolvaptan. However, the impact of goreisan on urine electrolytes remains uncertain. Methods: Patients with congestive heart failure who received goreisan as an add-on therapy to tolvaptan-incorporated medical therapy were prospectively included. The changes in urine parameters during the first 24 h were assessed as a primary concern. Baseline factors associated with an increase in urine sodium excretion were investigated. Results: A total of 21 patients were included. The median age was 81 (77, 86), and 13 (62%) were men. Twenty-four hours after the initiation of goreisan, urine osmolality decreased significantly, urine sodium level remained unchanged, urine potassium and glucose levels decreased significantly, urine urea nitrogen level tended to decrease, and urine volume tended to increase. The fractional excretion of sodium tended to increase. Baseline plasma B-type natriuretic peptide level had a positive correlation with a change in fractional excretion of sodium from baseline to day 1 (r = 0.52, p = 0.015). Conclusions: Goreisan may increase urine volume via aquaretic and natriuretic effects in patients with congestive heart failure receiving tolvaptan-incorporated medical therapy. Goreisan may have the ability to “modulate” fluid balance depending on congestion status. Full article