Background Vericiguat improves outcomes in heart failure with reduced ejection fraction (HFrEF), but its vascular and hemodynamic effects remain unclear. We explored changes in flow-mediated dilation (FMD) and invasive hemodynamics after vericiguat in symptomatic patients with HFrEF receiving guideline-directed medical therapy (GDMT). Methods In this single-center, open-label, single-arm exploratory pilot study, 10 patients with symptomatic HFrEF underwent assessment of FMD, right heart catheterization at rest and during 20-W supine exercise, echocardiography, laboratory testing, and 6-min walk distance (6MWD) before and after vericiguat. Vericiguat was uptitrated to 10 mg/day where tolerated. Results After treatment, FMD increased from 4.7 (3.0-6.1) to 6.9 (5.5-7.6)% ( P = .015), GLS improved from −6.8 (−8.6 to −5.5) to −9.0 (−10.5 to −6.7)% ( P = .009), resting cardiac output increased from 3.8 (3.6-5.4) to 4.6 (3.5-5.4) L/min ( P = .047), resting systemic vascular resistance decreased from 1664.1 (1327.2-1781.2) to 1293.1 (1143.6-1623.5) dyn·s·cm −5 ( P = .002), and 6MWD increased from 334.0 (251.3-395.0) to 355.0 (262.5-453.8) m ( P = .036). During 20-W exercise, cardiac output increased from 5.4 (4.6-5.9) to 6.5 (4.8-6.9) L/min ( P = .030), whereas exercise systemic vascular resistance showed only a decreasing trend ( P = .070). Conclusions In symptomatic patients with HFrEF receiving GDMT, vericiguat was associated with changes in peripheral vascular function and resting hemodynamic indices. However, exercise systemic vascular resistance did not improve significantly. These findings are exploratory and hypothesis-generating.
Background Cardiogenic shock remains a life-threatening condition with persistently high mortality. Norepinephrine and dopamine are commonly used vasoactive agents; however, comparative data on clinical outcomes remain limited. Methods This retrospective cohort study included 388 adults with cardiogenic shock treated with norepinephrine ( n = 72) or dopamine ( n = 316) at King Chulalongkorn Memorial Hospital, Thailand. The primary outcome was 28-day mortality. Survival was evaluated using Kaplan–Meier analysis and Cox proportional hazards regression. Inverse probability of treatment weighting (IPTW) was applied to adjust for confounding by indication. Results Mortality at 28 days occurred in 30.6% and 25.9% of the norepinephrine and dopamine groups, respectively. No statistically significant difference in 28-day mortality was observed in either the unadjusted (HR 0.84, 95% CI 0.52-1.34; P = .463) or IPTW-adjusted Cox proportional hazards model (HR 1.10, 95% CI 0.64-1.88; P = .725). Epinephrine rescue rates were comparable between groups (27.7% vs 24.2%; P = .551). Independent predictors of 28-day mortality included age ≥65 years, cardiopulmonary resuscitation, and epinephrine use ( P < .001 for all), as well as renal replacement therapy and endotracheal intubation ( P = .003 for both). Conclusion The present study did not demonstrate a significant difference in 28-day mortality between norepinephrine and dopamine; however, dopamine was associated with a significantly higher incidence of arrhythmias.
Background The ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease, Diabetes Mellitus, and Genotyping) score is a tool used to identify increased thrombotic risk in clopidogrel-treated patients. We evaluated the association between a low ABCD-GENE score (<10) and Bleeding Academic Research Consortium (BARC)-defined bleeding among prasugrel or ticagrelor and clopidogrel-treated patients. Methods This was an IRB-approved retrospective cohort study of patients who underwent percutaneous coronary intervention (PCI) and CYP2C19 genotyping. The primary outcome was time to first bleed of any severity within 1 year. Time to first major bleed, defined by BARC 3a, 3b, 3c, or 5 criteria, and major adverse cardiovascular events (MACE) were secondary outcomes. BARC bleeding events were compared between prasugrel or ticagrelor and clopidogrel-treated patients and stratified by the ABCD-GENE score threshold of ≥10. Kaplan-Meier and multivariable Cox proportional hazards model were used for time-to-event analyses. Results Of 2547 patients, 1760 were in the low score group, and 787 were in the high score group. Kaplan-Meier analysis showed that any bleeding ( P = .008) and major bleeding ( P = .015) were less for those with a low score compared to a high score. Among those in the low score group, any bleeding ( P < .001) and major bleeding ( P = .022) were lower with clopidogrel versus prasugrel or ticagrelor. However, the ABCD-GENE score was not independently associated with bleeding in the Cox model. No difference in MACE was observed by treatment in the low score group. Conclusions The ABCD-GENE score was associated with BARC bleeding, yet other variables had a greater impact such as history of GI bleed, anticoagulation, P2Y12 inhibitor, and age. Patients with a low score who received prasugrel or ticagrelor had more bleeding versus clopidogrel. Our findings support further evaluation of the ABCD-GENE score as a tool for guided P2Y12 inhibitor de-escalation post-PCI.
Background Platelet hyperactivity contributes to elevated cardiovascular risk in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter-2 inhibitors, including dapagliflozin, exert beneficial effects on platelet function and cardiovascular outcomes. As platelet microRNAs (miRNAs) are established during megakaryopoiesis, we aimed to characterize the platelet miRNA expression in T2DM and after dapagliflozin treatment. Methods Platelet miRNA profiles were compared between T2DM patients and controls using microarray, with qRT-PCR validation in an independent cohort (25 T2DM and 19 controls). T2DM patients were re-evaluated after 3-month dapagliflozin treatment. Results Exploratory microarray identified 602 candidate miRNAs with >2-fold differences between T2DM and control pools. qRT-PCR confirmed significant changes in miR-15b-3p, miR-146a-5p, miR-155-5p, and miR-223-3p (all q < 0.05), as well as nominally significant changes in miR-21-5p and miR-320a (both q = 0.052). In T2DM, miR-320a negatively correlated with mean platelet volume, platelet distribution width, and platelet large cell ratio, whereas miR-146a-5p showed positive correlations with platelet size parameters. Additionally, miR-21-5p positively and miR-223-3p negatively associated with soluble P-selectin. In an uncontrolled pre–post analysis, platelet miR-223-3p and miR-320a levels were significantly higher after dapagliflozin treatment. In silico target prediction yielded putative enrichment in pathways related to transcriptional regulation, insulin signaling, and autophagy, which likely reflects regulatory programs established in parent megakaryocytes and warrants functional validation. Conclusion Altered levels of miR-15b-3p, miR-146a-5p, miR-155-5p, and miR-223-3p are associated with platelet activation and maturation in T2DM patients. Dapagliflozin treatment may be associated with changes in platelet levels of miR-223-3p and miR-320a, hypothetically reflecting alterations in megakaryocytic programming during therapy.
Background The comparative effectiveness of angiotensin-converting enzyme inhibitors (ACEis) versus angiotensin receptor blockers (ARBs) in heart failure with nonreduced ejection fraction (HFnon-rEF) remains uncertain. We evaluated long-term outcomes of these therapies in a real-world cohort following hospitalization for acute heart failure. Methods This retrospective multicenter study (2005-2019) included 5837 patients with HFnon-rEF (left ventricular ejection fraction ≥ 40%). Patients were categorized by discharge prescription into ACEi, ARB, or non-renin-angiotensin system inhibitor (RASi) groups. A 14-day landmark approach ensured pharmacological stabilization and reduced time-related bias. Inverse probability of treatment weighting was used to balance covariates (SMD < 0.1). The primary outcome was a composite of cardiovascular (CV) death or heart failure rehospitalization at 1 year. Results The primary composite outcome was similar between ARB and ACEi users (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.75-1.17; P = .556). However, ARB therapy was associated with lower all-cause mortality compared with ACEi (adjusted HR, 0.74; 95% CI, 0.55-0.99; P = .041) and non-RASi (adjusted HR, 0.80; 95% CI, 0.67-0.94; P = .008). Subgroup analyses showed generally consistent directional associations between ARB use and lower mortality, although these findings were exploratory. Conclusions In this real-world cohort of patients with HFnon-rEF, ARB use was associated with lower all-cause mortality compared with ACEi, despite similar CV outcomes. These findings do not establish superiority and should be interpreted as hypothesis-generating.
Background The extent and biological relevance of shared genetic architecture between myocardial infarction (MI) and heart failure (HF) remain incompletely understood. Methods We analyzed large-scale European-ancestry genome-wide association studies summary statistics for MI and HF. Genome-wide genetic correlation was estimated using linkage disequilibrium score regression, and polygenic overlap was quantified using MiXeR. Shared loci were identified via conditional and conjunctional false discovery rate (condFDR/conjFDR) approaches. Functional prioritization incorporated Functional Mapping and Annotation-based annotation, Bayesian fine-mapping, transcriptome-wide association studies (TWAS), FOCUS gene fine-mapping, and summary-level Mendelian randomization (SMR) integrating UKB-PPP proteomic data. Results Linkage disequilibrium score regression revealed a robust positive genetic correlation between MI and HF (rg = 0.494, P = 1.12 × 10 −15 ). MiXeR demonstrated substantial polygenic overlap, with approximately 90% of MI-associated variants shared with HF and strong concordance in effect direction. The cond/conjFDR analyses identified multiple pleiotropic loci, including novel HF-associated regions. Fine-mapping prioritized rs544366796 within the SLC22A2/SLC22A3 locus as a high-confidence candidate variant for MI based on posterior probability. The TWAS and FOCUS highlighted canonical MI genes (CDKN2B, CELSR2, BRAP, NBEAL1) and identified MYOZ1 as an HF-specific candidate gene. Proteome-wide SMR analysis provided statistical evidence consistent with apolipoprotein E being a shared protein influenced by variants associated with both MI and HF. Conclusion The MI and HF share substantial genetic liability characterized by strong polygenic overlap and pleiotropic loci. Our integrative analyses suggest a potential 2-stage genetic framework linking ischemic susceptibility to myocardial remodeling and HF progression, which should be interpreted as a hypothesis-generating conceptual model rather than direct evidence of temporal progression.
Background Dual antiplatelet therapy (DAPT) with aspirin and potent P2Y 12 inhibitors such as ticagrelor effectively reduces ischemic events but increases bleeding risk. In patients requiring long-term DAPT, switching from ticagrelor to a thienopyridine is often considered to reduce bleeding risk or address other clinical concerns. However, such switching may cause a transient reduction in platelet inhibition, raising concerns about thrombotic complications. In particular, evidence is limited regarding the optimal loading dose strategy for East Asian patients undergoing this transition. Methods In this randomized, open-label trial, 43 patients with acute coronary syndrome (ACS) who had received ticagrelor-based DAPT for > 6 months after stent implantation were randomized to clopidogrel 600 mg loading/75 mg maintenance, clopidogrel 300 mg loading/75 mg maintenance, or prasugrel 30 mg loading/5 mg maintenance. Platelet reactivity and inflammatory markers (MMP-2, MMP-9, TNF-α) were assessed at baseline, 48 h, and 5 days after switching. The primary endpoint was the proportion of patients achieving optimal platelet reactivity (OPR). Results The proportion of patients achieving OPR was similar among groups at baseline (p = 0.483), 48 h (p = 0.699), and 5 days (p = 0.729). No significant intergroup differences were observed in inflammatory marker levels at any time point. No major adverse cardiovascular events occurred during follow-up. Conclusions In stable ACS patients on long-term DAPT, switching from ticagrelor to either clopidogrel or prasugrel maintained consistent platelet inhibition and inflammatory profiles, indicating that these switching strategies produce comparable pharmacodynamic profiles in East Asian populations during the early post-switch period. Trial Registration This investigator-initiated pharmacodynamic study was not prospectively registered.
Despite significant advances in the management of myocardial infarction (MI), therapeutic options targeting upstream pathogenic mechanisms remain scarce. This study introduces a novel multiomics-to-drug discovery framework to identify and validate causal therapeutic targets for MI. We conducted a systematic two-sample Mendelian randomization (MR) analysis integrating expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) data from the IEU OpenGWAS database, with replication in the UK Biobank cohort. Causal inference was rigorously validated using HEIDI heterogeneity tests, Bayesian colocalization, bidirectional MR, and multivariate MR (MVMR) to account for potential confounders. Downstream applications were explored via protein-protein interaction (PPI) network analysis, phenome-wide association studies (PheWAS), and molecular docking simulations. Initial screening identified four candidate genes (BMP1, APOB, FABP2, and ALDH2) associated with MI risk in both discovery and replication cohorts. However, only BMP1 demonstrated consistent causal effects at both transcriptional and proteomic levels, passing all sensitivity analyses with no evidence of horizontal pleiotropy in PheWAS. Colocalization and bidirectional MR further confirmed BMP1 as a robust, independent causal driver of MI. Molecular docking revealed that UK-383367, a selective BMP1 inhibitor, exhibits high binding affinity to the BMP1 active site. While BMP1 is traditionally associated with extracellular matrix remodeling, this study provides the first genetic evidence establishing it as an independent causal risk factor for MI, distinct from conventional traits such as hypertension. By bridging causal genetic inference with structure-based drug prediction, we propose BMP1 inhibition, specifically via agents like UK-383367, as a promising therapeutic strategy to mitigate MI-related pathological remodeling.
Background Heart failure (HF) is common among older adults; however, data on phenotype distribution and real-world pharmacologic management remain limited. This study assessed the prevalence of guideline-directed medical therapy (GDMT) underuse across HF phenotypes and identified factors associated with GDMT underuse among older outpatients in Vietnam. Methods In this multicenter cross-sectional study, 504 outpatients aged ≥60 years with HF were enrolled. Patients were classified into HF with reduced ejection fraction (HFrEF), mildly reduced ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF). HFmrEF and HFpEF were combined as a non-HFrEF group for analysis. Multivariable logistic regression was performed to identify factors independently associated with GDMT underuse. Results HFrEF, HFmrEF, and HFpEF accounted for 54.6% ( n = 275), 13.3% ( n = 67), and 32.1% ( n = 162) of patients, respectively. GDMT underuse was observed in 49.8% of patients with HFrEF and 38.0% of those with non-HFrEF phenotypes. In HFrEF, hypertension was associated with lower GDMT underuse (odds ratio [OR] 0.38; 95% confidence interval [CI] 0.15-0.98), whereas chronic obstructive pulmonary disease (COPD) was associated with higher underuse (OR 4.42; 95% CI [1.38-14.2]). In non-HFrEF, diabetes mellitus was independently associated with lower GDMT underuse (OR 0.52; 95% CI [0.30-0.91]). Conclusion In this study, GDMT underuse was observed in nearly half of patients with HFrEF and over one-third of those with non-HFrEF phenotypes. In HFrEF, hypertension was associated with lower GDMT underuse and COPD with higher GDMT underuse, whereas in non-HFrEF, diabetes mellitus was independently associated with lower GDMT underuse.
Background Hypertension remains a leading modifiable risk factor for cardiovascular disease, and effective anti-hypertensive prescribing is essential for optimal management. This study will evaluate the patterns of anti-hypertensive prescriptions, characteristics of specific drug class users, and significant factors influencing prescription choices within a Saudi Arabian cohort. Methods This retrospective, cross-sectional study at Al-Qatif Central Hospital included patients aged ≥40 years who attended outpatient cardiology and internal medicine clinics between January 2020 and December 2021. The characteristics of anti-hypertensive medication users and nonusers were compared using descriptive statistics. Logistic regression models were performed to identify factors associated with anti-hypertensive prescribing patterns adjusted for significant covariates, with results presented as adjusted odds ratios (OR) and corresponding 95% confidence interval (95% CI). Results About 62% of 5,852 patients were prescribed anti-hypertensive medication, with beta blockers (BBs) and calcium channel blockers (CCBs) being the most prescribed. BBs were primarily prescribed as monotherapy, constituting for 24% of prescriptions. Older patients (≥65 years) were more likely to receive combination therapy, with 17% receiving four anti-hypertensives medications. Diabetes mellitus was positively associated with the prescription of angiotensin receptor blockers (OR = 1.2, P < 0.05) and negatively associated with BBs prescribing (OR = 0.6, P < 0.05). Constipation exhibited a significant association with CCBs prescribing (OR = 1.4, P < 0.05). Conclusion This study demonstrates significant deviations from existing clinical guidelines, notably the overprescription of BBs in the management of hypertension. The findings highlight where doctors need to look more closely at their prescribing habits and suggest to promote the alignment of prescribing practices with emerging evidence-based recommendations.
Background Acute coronary syndrome (ACS) remains a leading cause of mortality globally. Dual antiplatelet therapy (DAPT) is standard after percutaneous coronary intervention (PCI). While ticagrelor has demonstrated favorable myocardial effects in preclinical studies, limited clinical data compared its impact on left ventricular (LV) remodeling versus clopidogrel. Objective To evaluate and compare the effect of ticagrelor and clopidogrel on LV remodeling among ACS patients post-PCI. Methods Eligible participants were adults (≥18 years) with confirmed ACS who were prescribed ticagrelor or clopidogrel for at least 3 months after PCI and had complete echocardiographic data at baseline and within one-year follow-up. Patients with missing follow-up imaging, switching between antiplatelets, contraindications to DAPT, or noncompliance were excluded. Echocardiographic parameters—LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF)—and B-type natriuretic peptide (BNP) were assessed, and multivariable regression models adjusted for confounders. Results A total of 137 patients met criteria (87 on ticagrelor, 50 on clopidogrel). Ticagrelor was associated with an adjusted LVEDV reduction of 8.17 mL compared with clopidogrel (95% CI −15.84 to −0.50; P = .039), an LVESV reduction of 8.09 mL (95% CI −13.88 to −2.29; P = .007), and a greater LVEF improvement of 4.05% (95% CI 2.41-5.70; P < .001). The reduction in BNP was also greater with ticagrelor by 73.56 pg/mL (95% CI −144.08 to −3.05; P = .043). Conclusion Ticagrelor was associated with more favorable LV remodeling parameters compared with clopidogrel in this cohort. These findings warrant confirmation in randomized trials.
Background In patients with heart failure (HF), loop diuretics (LD) are recommended to relieve congestion and may be de-escalated if symptoms improve. However, long-term use of the same LD dose is sometimes required owing to potential congestion exacerbation. Therefore, we investigated the factors associated with LD de-escalation in patients with acute decompensated HF (ADHF) and the relationship between this de-escalation and initiating guideline directed medical therapy (GDMT) during hospitalization. Methods In this retrospective cohort study, patients with ADHF who were prescribed LD and GDMT at discharge were included. The primary endpoint was LD de-escalation at 6 months post-discharge. Factors associated with this de-escalation were extracted using multivariate analysis. The Cochran–Armitage trend test was used to analyze the relationship between the number of GDMT initiated during hospitalization and LD de-escalation. Results Of 193 eligible patients, 40.4% underwent LD de-escalation. Significant de-escalation-associated factors were age <75 years (odds ratio, 2.114; 95% confidence interval, 1.125-3.972), body mass index (BMI) ≥ 22.0 kg/m 2 (2.022; 1.073-3.811), and no atrial fibrillation (1.948; 1.047-3.625). The LD de-escalation rate tended to increase with the number of angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonists, and sodium-glucose transporter 2 inhibitors initiated during hospitalization ( P = .013). Conclusion Younger age, high BMI, and no atrial fibrillation were LD de-escalation-associated factors in patients with ADHF. LD de-escalation post-discharge may occur more frequently if the number of GDMT with diuretic effects was increased during hospitalization.
Objectives To characterize the rs1042034 allele distribution in Vietnamese adults with untreated hypercholesterolemia and evaluate its impact on baseline lipid profiles and the early lipid-lowering response to rosuvastatin 20 mg. Materials and Methods In this cross-sectional exploratory study, 79 adults with low-density lipoprotein cholesterol [LDL-C] ≥ 3.4 mmol/L were enrolled and treated with rosuvastatin 20 mg plus lifestyle advice for 3 months. Genotypes were determined by TaqMan real-time PCR with Sanger sequencing validation. Baseline and 3-month lipid panels (LDL-C, high-density lipoprotein cholesterol [HDL-C], total cholesterol, non-HDL-C, triglycerides) were measured. Between-group comparisons used Kruskal–Wallis/ANOVA as appropriate; analysis of covariance (ANCOVA) models adjusted for baseline values assessed genotype (TT vs. CT + CC) effects on posttreatment lipids. Multivariable linear regression examined age, sex, and body-mass index as predictors; false discovery rate correction was applied. Results Baseline lipid concentrations did not differ significantly by genotype (overall LDL-C 4.37 ± 0.62 mmol/L; total cholesterol 6.62 ± 0.77 mmol/L). After three months, LDL-C reductions differed markedly by genotype ( P < .001): median absolute reductions were −0.47 mmol/L (TT; fractional −9.7%), −1.12 mmol/L (CT; −28.1%) and −1.28 mmol/L (CC; −29.8%). HDL-C change also differed ( P = .049) with medians 0.09, 0.24 and 0.15 mmol/L for TT, CT and CC, respectively. ANCOVA (adjusting for baseline) showed the TT genotype was independently associated with higher posttreatment LDL-C (β = 0.758; P = .001), lower posttreatment HDL-C (β = −0.121; P = .004), and higher TC (β = 0.482; P = .026) and non-HDL-C (β = 0.566; P = .007); TG was not affected ( P = .751). Conclusions This study provides preliminary evidence that APOB rs1042034 polymorphism significantly influences rosuvastatin efficacy in Vietnamese patients with hypercholesterolemia.
Doxorubicin (DOX)-induced cardiotoxicity significantly impairs cancer patient survival rates. Eleutheroside E (EE), a polyphenolic compound with established cardioprotective properties against high-altitude myocardial injury and ischemia/reperfusion damage, has not previously been investigated in the context of DOX-induced cardiac toxicity. This study aimed to elucidate the therapeutic potential of EE against DOX-associated cardiotoxicity and its underlying mechanisms. Cardiomyocyte viability was quantified using the CCK-8 assay and Hoechst 33342/PI dual staining. Cardiac function was evaluated by echocardiography. Morphological alterations in cardiomyocytes were analyzed through phalloidin, hematoxylin-eosin (H&E), and wheat germ agglutinin staining. Ferroptosis-related biomarkers including malondialdehyde (MDA), Ptgs2 mRNA levels, Fe2+ concentration, and lipid peroxidation were assessed respectively. EE administration attenuated DOX-induced cardiomyocyte atrophy in-vitro and improved cardiac function in-vivo. Mechanistically, EE counteracted DOX-mediated suppression of Nrf2 expression and inhibited ferroptosis via activation of the Nrf2/SLC7A11/GPX4 signaling axis. siRNA-mediated Nrf2 knockdown partly abolished EE's cardioprotective effects. These findings conclusively demonstrate that EE mitigates DOX-induced cardiotoxicity through Nrf2-dependent ferroptosis regulation, highlighting its therapeutic potential for preventing chemotherapy-associated cardiac complications.
Background Cardiovascular disease remains the first major reason for death in global, and hypertension is one very usual risk factor for this disease. Chemokine (CXC motif) ligand 13 (CXCL13) exhibits a crucial role in the development and angiogenesis of a variety of diseases. However, the impacts of CXCL13 in the amelioration of hypertension and the associated regulatory mechanisms have rarely reported. Methods The hypertensive rat model was induced by Ang II treatment. The protein and mRNA expressions were measured through western blot and RT-qPCR. The systolic blood pressure was monitored. The ET-1 level was examined through the commercial kit. The thickness of vascular elasticity layer was observed through hematoxylin eosin staining. The levels of angiotensin-converting enzyme (ACE), thiobarbituric acid-reactive substances (TBARS), and brain natriuretic peptide (BNP) were inspected through the commercial kits. Results CXCL13 exhibited high protein and mRNA expressions in hypertensive rat model. Knockdown of CXCL13 improved vascular remodeling and elevated blood pressure in hypertensive rat model. Moreover, suppression of CXCL13 protected heart in hypertensive rat model through declining the levels of ACE, TBARS, and serum BNP. Next, it was demonstrated that CXCL13 modulated the PF4V1/NF-κB pathway. Eventually, through rescue assays, it was proved that CXCL13 ameliorated hypertension through affecting PF4V1. Conclusion This study manifested that knockdown of CXCL13 improved vascular remodeling, reduced blood pressure, and protected the heart by affecting the PF4V1/NF-κB signaling pathway in a hypertensive rat model. This discovery may offer novel opinions in the treatment of hypertension.
Background The therapeutic potential of the human amnion has been known since the early twentieth century. Subsequent study has revealed the further therapeutic potential of all elements of the amnion—membrane, cells, fluid—in the treatment of cardiac disease. Materials and Methods A systematic review was performed utilizing PubMed/MEDLINE and Embase with search terms including “amniotic fluid,” “cardiovascular disease,” “cardiac disease,” “amnion,” “amniotic membrane,” and “heart.” Results were reviewed by each author to ensure inclusion of all relevant articles. Animal studies were included for evaluation of existing preclinical models, and the few available clinical studies of amniotic products were included. Results Preclinical studies addressing organ function, assessment, and enhancement of cardiac performance in response to injury, and regenerative potential are included, as are the few clinical studies utilizing amniotic products for the treatment of cardiac disease. Therapeutic approaches include reduction of inflammation, immunomodulation, and the promotion of myocardial regeneration via cellular therapy to target the most common mechanisms underlying myocardial injury. Conclusions The components of the human amnion have anti-inflammatory, immunomodulatory, and pro-differentiation abilities which lend the ability to attenuate myocardial ischemia-reperfusion injury, temper cardiac fibrosis, and promote activation of progenitor cells to induce regeneration. Preclinical studies have focused heavily on cellular therapy, but clinical experience has yielded little success. The acellular components of the amnion have fueled more recent investigation and represent a new source of enthusiasm for clinical translation of amniotic products in the treatment of cardiac disease.
IntroductionAprocitentan, is an orally active, once-daily administered, dual endothelin receptor antagonist that was recently approved for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs.MethodsThe potential of aprocitentan to affect the QT interval was investigated in this thorough QT/QTc study that was performed as a multiple-dose, randomized, double-blind, placebo- and moxifloxacin-controlled (open-label), crossover study in healthy male and female subjects. Concentration-QT modeling, using a linear mixed-effects model, was performed on data extracted from continuous Holter electrocardiogram recordings.ResultsOf the 48 subjects enrolled in the study, 32 subjects completed study treatment. The main reasons for stopping study treatment were the occurrence of adverse events and withdrawal of consent. The dosing regimen of 25 mg aprocitentan o.d. (the highest approved therapeutic dose in the European Union; Cmax = 3.68 µg/mL) was safe and well tolerated; the supratherapeutic dosing regimen of 100 mg aprocitentan o.d. showed limited tolerability. Results indicated that ΔΔQTcF increased with increasing aprocitentan concentrations. The predicted upper bound of the 2-sided 90% ΔΔQTcF confidence interval exceeded the 10 ms threshold of regulatory concern at 16.10 µg/mL, which was close to the geometric mean maximum concentration (ie, 16.77 µg/mL) obtained with a 100 mg supratherapeutic dose.ConclusionsAt the highest therapeutic dose of 25 mg, there was no clinically significant prolongation of QTc. The risk of QT prolongation with therapeutic doses of aprocitentan is considered low.
