Journal of Cardiovascular Pharmacology最新文献

Abstract: Patients with ST-segment elevation myocardial infarction (STEMI) and complex coronary artery disease (CAD) face a poor prognosis, including increased heart failure (HF) risk. Phase 2 clinical trials of anakinra have shown inhibition of the acute inflammatory response and prevention of HF after STEMI, but data on its effects based on CAD complexity are lacking. We performed a pooled secondary analysis of 139 patients with STEMI. The SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery), SYNTAX II, and Gensini scores were calculated, and patients were divided into 2 groups below and above the median. We evaluated the effect of anakinra on the area-under-the-curve of high-sensitivity C-reactive protein (hsCRP-AUC) at 14 days, and the composite endpoint of new-onset HF, HF hospitalization, or all-cause death at 1-year follow-up using Kaplan-Meier survival curves, Cox regression analysis for hazard ratios (HRs), and tested interactions between subgroups. All 3 CAD complexity scores (SYNTAX, SYNTAX II, and Gensini) were associated with an increased risk of adverse events (HR 1.02-1.06, all P-values ≤0.025). We found no statistically significant interactions between CAD extent, measured as single-vessel or multivessel CAD, SYNTAX score ≤9 or >9, SYNTAX II score ≤24 or >24, Gensini score ≤32 or >32, and treatment effect of anakinra on hsCRP-AUC or the composite clinical endpoint (all P - values for interaction >0.05). In conclusion, among patients with STEMI, IL-1 blockade with anakinra significantly attenuated the acute inflammatory response and reduced the risk of HF-related events regardless of the spectrum of CAD complexity.

Abstract: Transthyretin amyloidosis (ATTR) is characterized by the deposition of unstable transthyretin protein (TTR) in the heart or peripheral nerves. Therapeutic strategies for ATTR include inhibition of the secretion of abnormal TTR by the liver, reducing the concentration of aberrant TTR in the circulation, and eliminating amyloid deposits of TTR in tissues. This article delves into the pathogenesis of TTR secretion from the liver into the bloodstream, its deposition in tissues, and the subsequent development of ATTR. In addition, we delineated the advancements in treatment strategies and discussed future research directions to provide novel insights for the identification of diagnostic and preventive targets.

Despite the wide-spread use of beta blockers, unpredictable response and overall low efficacy are the major pitfalls of beta blocker use for premature ventricular complexes (PVC). Accordingly, we aimed to reveal Holter-guided electrocardiographic criteria to predict the beta blocker responder ones of PVCs. A total of 89 patients who had pre- and post- treatment Holter ECG recordings and fulfilled the inclusion criteria were retrospectively included in the study. Holter recordings were screened for heart rate variability (HRV), numbers of PVC, heart rate, pre and post coupling intervals (CI) in three different time intervals (24:00 to 08:00am, 08:00 am to 16:00 pm and 16:00pm to 24:00) . Forty three patients were defined as beta blocker responder group in respect to 70% decrease in PVCs burden. HRV analysis revealed that there were not statistically significant differences between beta blocker responder and non-responder group. CI ratio ((post-PVC CI+ pre-PVC CI)/Pre-PVC CI) of responder and non-responder groups in 24.00 to 8.00 am time interval was statistically different (3.19 vs. 2.91, p=0.006 respectively). Logistic regression analysis revealed that CI ratios of the PVCs during the 24:00-08:00 am intervals have significantly associated with the beta blocker responsiveness for PVCs (Odds ratio: 9.54 95% CI: 1,89-48.7, P value: 0.006) Night-time increased CI ratio i.e shorter CI time has been found to be an independent predictor of beta blocker response against PVCs. Therefore, beta blockers may be preferably recommended for PVCs, especially in those with shorter CI or increased CI ratio.

Serotonin (5-hydroxytryptamine, 5-HT) at low plasma concentrations reduces blood pressure and dilates some skeletal muscle arterioles in the rat. We hypothesized that the 5-HT7 receptor is essential for both 5-HT-induced changes in blood pressure and skeletal muscle arteriolar function. Male 5-HT7 receptor knock out (KO) rats under isoflurane anesthesia had a higher resting hindquarter vascular resistance [HQVR; mm Hg/ml/min; KO (16.0+2.0) vs WT (10.8+0.6.0), p = 0.04]; this was not observed in females. The reduction in blood pressure and HQVR caused by intravenous infusion of 5-HT (25 μg/kg/min) was attenuated (∼56%) in male and female KO rats vs WT. Left anterior descending (LAD) coronary arterial ligation was used to create a model of impaired hindquarter perfusion and exercise intolerance. The goal was to determine whether heart failure associated skeletal muscle blood flow abnormalities were affected by loss of a functioning 5-HT7 receptor in skeletal muscle vasculature. Transdermal neuromuscular electrical stimulation (NMES) was used to mimic exercise induced contraction of skeletal muscle and increase blood flow in the hindquarters (HQ). Male (M) and female (F) 5-HT7 receptor KO rats had a profoundly reduced ability to increase HQ flow during NMES vs WT (% increase from basal; M WT = 118.0+18.0 vs KO=14.6+7.1%; F WT= 101.0+12.0 vs KO = 7.6+6.0%), observed in sham and LAD rats. In a naive cohort of 5-HT7 WT and KO rats, NMES-induced increases in HQ flow did not occur in 5-HT7 receptor KO rats. The NMES-induced increase in HQ flow was also abolished in the presence of the 5-HT7 receptor antagonist SB269970 in normal Sprague-Dawley rats. Lectin visualization of gastrocnemius muscle microvasculature indicateded that the elevated HQVR at rest in male 5-HT7 receptor KO rats was not due to a reduced microvascular density vs the WT. We conclude that 5-HT acting at least in part via the 5-HT7 receptor may have a larger role in (patho)physiological regulation of the circulation than has been heretofore appreciated.

Immuno-cardiology is an emerging field that explores the interplay between the immune system, inflammation and cardiovascular health/disease, aiming to develop innovative therapies for preventing and treating cardiac diseases. Indeed, chronic inflammation and immune dysregulation play pivotal roles in most cardiovascular conditions, including arrhythmias, atherothrombosis, ischemic heart disease, heart failure, and valve disease. Recent advances in immune-based therapies, including chimeric antigen receptor (CAR)-T and CAR-macrophage (CAR-M) technologies, have demonstrated potential in impacting on cardiac fibrosis and thus improving surrogate endpoints in preclinical studies. Immune checkpoint inhibitors (ICIs), while already established as an effective intervention in oncology, present challenges in their cardiovascular applications due to cardiotoxic side effects, highlighting the need for dedicated cardioprotective strategies or further molecular refinements. Nanoparticle-based delivery systems and cytokine-targeted therapies may offer precise modulation of immune responses, while gut microbiota interventions could exploit the systemic impact of inflammation on cardiovascular health. Despite these quite promising advances, barriers such as safety, scalability, and patient-specific responses must be addressed, and thus precision and personalized approaches will be crucial to overcoming these challenges and ensuring safe and also equitable access. By leveraging interdisciplinary collaboration and technological innovations, immuno-cardiology holds the promise of transforming the prevention and treatment landscape for cardiac diseases, paving the way for improved outcomes and quality of life for patients worldwide.

Procyanidin B2 (PB2) is a prominent procyanidin isomer. Its effects and mechanisms in cardiac remodeling are not fully understood. Peroxisome proliferator-activated receptor gamma (PPAR-γ) plays a crucial role in regulating cardiac hypertrophy, fibrosis, and inflammation. This study aims to investigate the effect of PB2 on pathological cardiac fibrosis and inflammation, focusing on the underlying mechanisms involving PPAR-γ. In vitro, cardiac fibrosis was induced in cardiac fibroblasts using angiotensin II. In vivo, a mouse model of pathological cardiac fibrosis was generated through transverse aortic constriction to induce pressure overload. We found that PB2 inhibited proliferation, differentiation, collagen accumulation, and the NF-κB inflammation pathway in cardiac fibroblasts triggered by angiotensin II. These inhibitory effects were negated by the PPAR-γ antagonist GW9662 and RNA interference. Additionally, PB2 directly elevated PPAR-γ expression in cardiac fibroblasts. Similarly, PB2 alleviated transverse aortic constriction-induced cardiac dysfunction, myocardial fibrosis, and inflammation in mice. These cardioprotective effects of PB2 in vivo were counteracted by co-administration with GW9662. Correspondingly, the upregulation of PPAR-γ protein expression by PB2 in pressure-overloaded hearts was also counteracted by GW9662 co-administration. In conclusion, this study demonstrates that PB2 exerts protective effects against pathological cardiac fibrosis and inflammation through a PPAR-γ dependent mechanism.

The NC1 domains of collagens have been shown to possess antiangiogenic potential and, therefore, are of therapeutic interest for cancer. However, endostatin and other NC1 domains have not been successful in clinical tests. Therefore, we used evolutionary conservation to perform molecular deconstruction of the domains to further understand their structure-activity relationship, thereby deciphering their antiangiogenic potential. Homology exploration revealed that collagen type X contains a highly interesting NC1 domain (decastatin), with several sequences showing significant homology with vastatin, which is a known collagen type VIII-derived NC1 domain. For comparison, endostatin and vastatin were split into fragments, some of which contained highly conserved regions. The testing of these peptides revealed that the peptides containing conserved regions induced signaling, and fragment four of decastatin showed the highest potency of all fragments, with a calculated IC 50 value of 2.7 μM in the human umbilical vein endothelial cell (HUVEC)-based tube formation assay, which is like that of an intact NC1 domain. Notably, the corresponding fragment from vastatin (V4) also inhibited tube formation, suggesting that this region is of therapeutic interest. In summary, we used evolutionary conservation to identify a novel NC1 domain of collagen type X, a collagen playing a role in angiogenesis of the growth plate. Furthermore, we provided data indicating that the antiangiogenic activity of NC1 domain-derived peptides reside within their conserved domains. As a result, we identified a fragment called Decastatin fragment 4 (D4) derived from the NC1 domain of collagen type X, and which has potent antiangiogenic activity.