Cardiology and Therapy最新文献

Numerous genetic and epidemiologic studies have demonstrated an association between elevated levels of lipoprotein(a) (Lp[a]) and cardiovascular disease. As a result, lowering Lp(a) levels is widely recognized as a promising strategy for reducing the risk of new-onset coronary heart disease, stroke, and heart failure. Lp(a) consists of a low-density lipoprotein-like particle with covalently linked apolipoprotein A (apo[a]) and apolipoprotein B-100, which explains its pro-thrombotic, pro-inflammatory, and pro-atherogenic properties. Lp(a) serum concentrations are genetically determined by the apo(a) isoform, with shorter isoforms having a higher rate of particle synthesis. To date, there are no approved pharmacological therapies that effectively reduce Lp(a) levels. Promising treatment approaches targeting apo(a) expression include RNA-based drugs such as pelacarsen, olpasiran, SLN360, and lepodisiran, which are currently in clinical trials. In this comprehensive review, we provide a detailed overview of RNA-based therapeutic approaches and discuss the recent advances and challenges of RNA therapeutics specifically designed to reduce Lp(a) levels and thus the risk of cardiovascular disease.

Introduction: Trinidad & Tobago has the highest prevalence of cardiovascular disease (CVD) in the Caribbean and clopidogrel is a ubiquitously used treatment. Yet, the extent of genetically mediated clopidogrel resistance is unknown. To determine this, we investigated whether the association between CYP2C19*2 and CYP2C19*3 genetic variants and clopidogrel resistance holds, and calculated the frequencies of these in the Trinidadian CVD population.

Methods: Demographic data, clinical data, and a saliva sample were collected under informed consent from 22 patients with CVD on dual anti-platelet therapy whose biochemical resistance to clopidogrel is known, and a further 162 patients accessing the main public CVD clinic in Trinidad and who are either currently being treated or are likely to be treated with clopidogrel. A polymerase chain reaction (PCR) and restriction enzyme digestion procedure was used to genotype each patient for the CYP2C19*2 and CYP2C19*3 allelic variants. Genotype was compared to known clopidogrel resistance in the 22 patients, and to disease status and clopidogrel usage in the larger cohort.

Results: CYP2C19*2 genotype was concordant with clopidogrel resistance. CYP2C19*2 was detected in 61.1% (99/162) of patients and CYP2C19*3 was undetected. Clopidogrel was the most prescribed antiplatelet therapy (42%). A total of 120 people presented with coronary artery disease (CAD) and 52.5% of these (n = 63/120) are currently prescribed clopidogrel. 63.5% (40/63) of patients with CAD who are prescribed clopidogrel carry the CYP2C19*2 allele; ten homozygous and 30 heterozygous. Indian patients comprised 65% of the cohort and were four times more likely to carry the CYP2C19*2 allele than African patients.

Conclusions: A large proportion of Trinidadian patients with CVD who are prescribed or may be prescribed clopidogrel carry genetic variants associated with clopidogrel resistance. These results emphasize the clinical need for further investigation into whether CYP2C19*2 genotype should guide clopidogrel use for the cardiovascular disease population in Trinidad & Tobago. A slide deck is available for this article.

Anticoagulation therapy has undergone significant evolution, marked by the emergence of direct oral anticoagulants with distinct advantages. Despite these advancements, challenges persist in managing residual thrombotic and bleeding risks, particularly among vulnerable populations. The pursuit of alternative drugs has honed in on factor XI/XIa inhibitors. This comprehensive review delves into several key aspects regarding this new target: (i) the role of factor XI in the coagulation cascade; (ii) the genetic evidence and pathophysiologic rationale supporting factor XI inhibition as a therapeutic target; (iii) an exploration of the various types of factor XI/XIa inhibitors currently under investigation; (iv) potential applications of these medications, spanning thromboprophylaxis after orthopedic surgery, stroke prevention in atrial fibrillation, secondary prevention after acute coronary syndrome, non-cardioembolic stroke, thromboprophylaxis after foreign material implantation, end-stage renal disease, and patients with cancer; and (v) an overview of ongoing studies, recent findings, and the future trajectory of research into these drugs.

Introduction: Limited data are available regarding the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) in patients experiencing major hemorrhage or requiring expeditious surgical intervention, both globally and within Japan.

Methods: We executed a prospective, observational post-marketing surveillance study of patients receiving 4F-PCC for the first time between September 19, 2017 and August 15, 2018 in Japan. Patients were subjected to a comprehensive follow-up for a duration of 4 weeks.

Results: Of 1381 eligible patients, 1271 (92%) received a vitamin K antagonist. Among these, 58% were aged ≥ 75 years, 49% manifested atrial fibrillation, 17% presented with valvular heart disease, and 6% exhibited venous thromboembolism. The median (range) international normalized ratio was 2.67 (0.96-27.11) at baseline and 1.21 (0.45-6.61) at first measurement post-administration of 4F-PCC. The most common reason for 4F-PCC administration was intracranial hemorrhage (59.6%), followed by gastrointestinal bleeding (6.6%). Hemostatic effectiveness was achieved in 85.8% of patients. The incidences of adverse drug reactions (ADRs) and serious ADRs were 3.9% and 2.8%, respectively. Thromboembolic events (TEEs) occurred in 20 (1.5%) patients, with a mean onset of 10 days. The majority of TEEs were classified as nervous system disorders (55%). At the time of TEE, only 13% of patients resumed anticoagulant therapy.

Conclusion: The incidence of TEEs following treatment with 4F-PCC did not surpass those observed in phase 3 trials. No novel safety signals were identified. The safety and effectiveness of 4F-PCC in Japanese real-world practice were in harmony with the observations of prior studies.

Introduction: Fetal echocardiograms (F-echo) are recommended in all pregnancies when maternal congenital heart disease (CHD) is present, even if there was a prior level II ultrasound (LII-US) that was normal. The goal of this study was to evaluate if any diagnosis of a critical CHD was missed in a fetus with maternal CHD who had a normal LII-US.

Methods: A retrospective chart review of all F-echoes where the indication was maternal CHD between 1/1/2015 to 12/31/2022 was performed. Fetuses were included if they had a LII-US that was read as normal and had an F-echo. Critical CHD was defined as CHD requiring catheterization or surgical intervention < 1 month of age.

Results: A total of 296 F-echoes on fetuses with maternal CHD were evaluated, of which 175 met inclusion criteria. LII-US was performed at 19.8 ± 2.9 weeks gestational age and F-echo was performed at 24.2 ± 2.8 weeks gestational age. No patient with a normal LII-US had a diagnosis of a critical CHD by F-echo (negative predictive value = 100%). Evaluating those patients that had a negative LII-US, ten patients were diagnosed with non-critical CHD postnatally (negative predictive value = 94.3%). F-echo correctly diagnosed two of the ten missed LII-US CHD.

Conclusions: Critical CHD was not missed with a normal LII-US in this at risk population. F-echo also missed the majority of CHD when a LII-US was read as normal. A cost-benefit analysis of screening F-echo in fetuses with maternal CHD should be conducted if a normal LII-US has been performed.

Introduction: The 2021 Canadian Cardiovascular Society (CCS) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with atherosclerotic cardiovascular disease (ASCVD). For patients above LDL-C threshold on maximally tolerated statins, adding ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is recommended. This population-based, real-world study examined cardiovascular (CV) events in patients with ASCVD who are on statins and above current guideline threshold LDL-C levels.

Methods: Using administrative health data in Alberta, Canada, we identified patients with myocardial infarction (MI), ischemic stroke (IS), or peripheral artery disease with LDL-C > 1.8 mmol/L on statins between April 1, 2010 and March 31, 2016. Exploratory subgroups included very high-risk patients with ASCVD shown to derive the most benefit from PCSK9i intensification as identified by the CCS guidelines, including those with acute coronary syndrome (ACS) or recent MI. Frequencies and rates of individual and composite CV events (primary outcome: MI, IS, hospitalization for unstable angina, coronary revascularization, cardiovascular death; secondary outcome: MI, IS, CV death) were calculated over follow-up.

Results: The study included 32,984 patients with a mean (standard deviation) follow-up of 40.8 (21.0) months. Overall, 17.7% and 15.6% experienced a primary and secondary outcome, respectively, with rates of 5.58 and 4.83 per 100 patient-years, respectively. CV death and MI were the most common events. Subgroups with recurrent MI and comorbid diabetes exhibited higher CV event rates (23.6% and 22.2% had a primary outcome, respectively). Rates of CV events were notably high in patients with ACS or recent MI (49.4% and 54.0% had a primary outcome, respectively).

Conclusion: This real-world study confirms that statin-treated high-risk patients with ASCVD and above-threshold LDL-C levels have substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to reduce CV risk.

Introduction: Cardiovascular diseases (CVD) are the leading cause of death globally. Inflammation is an important driver of CVD where tissue damage may lead to the formation of deadly thrombi. Therefore, antithrombotic drugs, such as platelet inhibitors, are crucial for secondary risk prevention in coronary artery disease (CAD) and peripheral artery disease (PAD). For severe forms of the disease, dual-pathway inhibition (DPI) where low-dose aspirin is combined with rivaroxaban has shown improved efficacy in reducing cardiovascular mortality.

Methods: Given this greater improvement in mortality, and the importance of inflammation in driving atherosclerosis, the potential for off-target inflammation-lowering effects of these drugs was evaluated by looking at the change in immune cell distribution and responsiveness to ex vivo lipopolysaccharide (LPS) stimulation after 3 months of DPI in patients with CAD.

Results: We observed no changes in whole blood or peripheral blood mononuclear cell (PBMC) immune cell responsiveness to LPS after 3 months of DPI. Additionally, we did not observe any changes in the distribution of total white blood cells, monocytes, neutrophils, lymphocytes, or platelets during the study course. Signs of systemic inflammation were studied using Olink proteomics in 33 patients with PAD after 3 months of DPI. No changes were observed in any of the inflammatory proteins measured after the treatment period, suggesting that the state of chronic inflammation was not altered in these subjects.

Conclusion: Three months of DPI does not result in any meaningful change in immune cell responsiveness and distribution in patients with CAD or PAD.

Trial registration: ClinicalTrials.gov ID: NCT05210725.

Introduction: The aim of this sub-study was to evaluate the relationship between echocardiography (echo) and cardiac magnetic resonance imaging (cMRI) variables and to utilize echo to assess the effect of macitentan on right ventricle (RV) structure and function.

Methods: REPAIR (NCT02310672) was a prospective, multicenter, single-arm, open-label, 52-week, phase 4 study in pulmonary arterial hypertension (PAH) patients, which investigated the effect of macitentan 10 mg as monotherapy, or in combination with a phosphodiesterase 5 inhibitor, on RV structure, function, and hemodynamics using cMRI and right heart catheterization. In this sub-study, patients were also assessed by echo at screening and at weeks 26 and/or 52. Post hoc correlation analyses between echo and cMRI variables were performed using Pearson's correlation coefficient, Spearman's correlation coefficient, and Bland-Altman analyses.

Results: The Echo sub-study included 45 patients. Improvements in echo-assessed RV stroke volume (RVSV), left ventricular SV (LVSV), LV end-diastolic volume (LVEDV), RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and in 2D global longitudinal RV strain (2D GLRVS) were observed at weeks 26 and 52 compared to baseline. There was a strong correlation between echo (LVSV, 2D GLRVS, and LVEDV) and cMRI variables, with a moderate correlation for RVSV. Bland-Altman analyses showed a good agreement for LVSV measured by echo versus cMRI, whereas an overestimation in echo-assessed RVSV was observed compared to cMRI (bias of - 15 mL). Hemodynamic and functional variables, as well as safety, were comparable between the Echo sub-study and REPAIR.

Conclusions: A good relationship between relevant echo and cMRI parameters was shown. Improvements in RV structure and function with macitentan treatment was observed by echo, consistent with results observed by cMRI in the primary analysis of the REPAIR study. Echo is a valuable complementary method to cMRI, with the potential to non-invasively monitor treatment response at follow-up.

Trial registration number: REPAIR NCT02310672.

Cardiovascular disease is the primary cause of pregnancy-related mortality and morbidity in the United States, and maternal mortality has increased over the last decade. Pregnancy and the postpartum period are associated with significant vascular, metabolic, and physiologic adaptations that can unmask new heart failure or exacerbate heart failure symptoms in women with known underlying cardiomyopathy. There are unique management considerations for heart failure in women throughout pregnancy, and it is imperative that clinicians caring for pregnant women understand these important principles. Early involvement of multidisciplinary cardio-obstetrics teams is key to optimizing maternal and fetal outcomes. In this review, we discuss the unique challenges and opportunities in the diagnosis of heart failure in pregnancy, management principles along the continuum of pregnancy, and the safety of heart failure therapies during and after pregnancy.