Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study

In phase I KAT301 trial, intramyocardial adenovirus-mediated vascular endothelial growth factor -DΔNΔC (AdVEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved symptoms in refractory angina patients at 1-year follow-up without major safety concerns. We investigated the long-term safety and efficacy of AdVEGF-D GT. 30 patients (24 in VEGF-D group and 6 blinded, randomized controls) were followed for 8.2 years (range 6.3–10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse event (MACE) and other predefined safety endpoints. MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.97; 95% confidence interval 0.36–2.63; P = 0.95). Mortality and new-onset comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P = 0.006) but not in control group (2.2 vs. 2.6; P = 0.414). Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

Cardiovascular Issues in Tyrosine Kinase Inhibitors Treatments for Chronic Myeloid Leukemia: A Review

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by a fusion gene, encoding for the chimeric protein BCR-ABL, with constitutive tyrosine kinase activity. The use of tyrosine kinase inhibitors (TKIs) has drastically improved survival, but there are significant concerns about cardiovascular toxicity. Cardiovascular risk can be lowered with appropriate baseline evaluation, accurate choice of TKI therapy, improvement of modifiable cardiovascular risk factors through lifestyle modifications, and prescription of drugs for primary or secondary prevention. Which examinations are necessary, and when do they have to be scheduled? How often should a TKI-treated patient undergo which cardiology test or exam? Is there an accurate way to estimate the risk that each TKI may determine a cardiovascular adverse event in a CML patient? In a few words, how can we optimize the cardiovascular risk management in CML patients before and during TKI treatment? The aim of this review is to describe cardiac and vascular toxicity of TKIs used for CML treatment according to the most recent literature and to identify unmet clinical needs in cardiovascular risk management and complications in these patients. Regarding the TKI-induced cardiovascular toxicity, the full mechanism is still unclear, but it is accepted that different factors may play different roles: endothelial damage and atherosclerosis, metabolic impairment, hypertensive effect, glomerular impairment, and mast-cell disruption. Preventive strategies are aimed at minimizing cardiovascular risk when CML is diagnosed. Cardio-oncology units in specialized hematology centers may afford a personalized and multidisciplinary approach to the patient, optimizing the balance between treatment of the neoplasm and management of cardiovascular risk.

Relative Importance of Heart Failure Events Compared to Stroke and Bleeding in AF Patients

Introduction: Incident heart failure (HF), ischemic stroke and systemic embolism (IS/SE), and major bleeding related to anticoagulation therapy are still the most frequent events occurring in patients with atrial fibrillation (AF). The aim of this study was to assess the 3-year incidence, predictors, and related mortality of IS/SE, major bleeding, and HF in a large cohort of AF outpatients. Methods and results: We studied 4973 outpatients with prevalent AF included in the CARDIONOR registry. The mean age was 72.9 ± 11.2 years, 24.1% had diabetes mellitus and 78.9% had anticoagulant therapy at baseline. The mean CHA2DS2Vasc score was 3.4 ± 1.7. After a median follow-up of 3.2 years (IQR: 2.8 to 3.5), incident HF, IS/SE and major bleeding occurred in 10.5%, 3.3% and 2.1% of patients, respectively. When analyzed as time-dependent variables, IS/SE, major bleeding and hospitalization for decompensated HF were all strongly associated with mortality. The independent predictors of incident HF were age, women, hypertension, diabetes mellitus, coronary artery disease and a previous history of HF. A sensitivity analysis in patients without history of HF at inclusion revealed that incident HF remained the most frequent adverse event, occurring in 5.3% of patients, compared to IS/SE (1.7%) and major bleeding (2.5%). Conclusion: HF is a common residual cardiovascular adverse event occurring in AF outpatients and is associated with a very high mortality. Since modifiable risk factors are associated with incident HF, upstream intensive management of these risk factors would be of interest.

Abstract 16180: Cardiovascular Adverse Events Associated With Androgen Receptor-targeted Therapy Used in the Treatment of Prostate Cancer

Introduction: Prostate cancer is the second most common cancer in males. Its risk increases with age. So does the risk for cardiovascular disease. Androgen receptor-targeted therapy is now recommended to be added to androgen-deprivation therapy in the treatment of prostate cancer. We present common cardiovascular adverse events seen with the use of anti-androgens medication: abiraterone, enzalutamide, apalutamide, and darolutamide. Methods: We conducted a meta-analysis of 13 multinational randomized phase III clinical trials looking for cardiovascular adverse events in groups that received abiraterone, enzalutamide, apalutamide and darolutamide for treatment of prostate cancer. We analyzed a cohort of 9867 patients in these trials. Results: In the abiraterone usage group (n= 3492), most common cardiovascular adverse event was hypertension reported in 16.03%. Atrial fibrillation was reported in 0.97% and other cardiovascular events (IHD, MI, SVT, VT, and heart failure) were seen in 9.56%. In the enzalutamide usage group (n=4094) hypertension was seen in 10.6%, IHD in 1.88%, and atrial fibrillation was seen in 0.39%. Other unspecified cardiovascular adverse events were reported in 5.98%. In the apalutamide usage group (n=1327) hypertension was seen in 22%. Other cardiovascular adverse events (atrial fibrillation, MI, cardiogenic shock) were seen in 0.96%. In the darolutamide usage group (n=954) hypertension was seen in 6.6%, coronary artery disorders (coronary artery disease, coronary artery occlusion and stenosis) in 3.24%, and heart failure in 1.88%. Conclusions: The most common cardiovascular adverse event with use of anti-androgen medication seen in this large cohort analysis was hypertension with highest incidence seen in apalutamide group. Other cardiovascular side-effects noted were atrial fibrillation, SVT, VT, ischemic heart disease, MI, heart failure, and cardiogenic shock. Abiraterone and enzalutamide are the drugs that have been used in most trials. FDA adverse reaction reporting system (FAERS) shows hypertension as the most commonly reported cardiovascular adverse event with abiraterone and enzalutamide use. More prospective studies are needed to further access cardiovascular risk with use of anti-androgen therapy.

The Effect of Bay Leaf Extract (Syzygium polyanthum) on Reducing Overexpression of Matrix Metalloproteinases-13 in Acute Coronary Syndrome

AIM: The objective of the study was to determine the inhibitory effect of bay leaf (Syzygium polyanthum) on matrix metalloproteinases (MMPs) (MMP-9 and MMP-13) inhibitory effect in surgery-induced acute coronary syndrome (ACS) rat model. METHODS: This study was experimental animal study. Thirty-two surgery-induced ACS Wistar rats (Rattus norvegicus) divided into 16 bay leaf extract (treatment) group and 16 control groups were sacrificed on days 1, 3, 7, and 14 after induction. Expressions of MMP-9 and MMP-13 were determined by immunohistochemistry and its scoring was assessed by two-blinded experienced pathologists. The immunohistochemical scoring of MMP-9 and MMP-13 between groups was analyzed using independent sample t-test and within groups by using one-way ANOVA test. RESULTS: The expression of MMP-13 in treatment group was decreased compared to control group on days 7 and 14 (p = 0.001 and p = 0.015, respectively). Compared to day 1, the reduction expression of MMP-13 was significant in both control group and treatment group (p = 0.009 and p = 0.003, respectively). There were no significant changes in expression of MMP-9 between groups, and within control group and treatment group. CONCLUSION: Bay leaf can reduce the overexpression of MMP-13 in surgery-induced ACS rat model. Bay leaf extract can be considered to be given as an adjuvant to prevent cardiovascular adverse event and adverse cardiac remodeling post-ACS.

Carfilzomib: A Tale of a Heartbreaking Moment: Case Report and Concise Review of the Literature

Background: Carfilzomib, a proteasome inhibitor, known as a therapeutical option for people who have already received one or more previous treatments for multiple myeloma, has well known cardiac and systemic adverse effects. Objective: There is evidence supporting that adverse effects are dose dependent, yet there is no known patient phenotype characterized by worse associated consequences, nor are there widely accepted monitoring protocols. Results: In this article we describe two patients with cardiovascular adverse events related to carfilzomib treatment and their clinical course. Our goal was to present two cases of daily practice, which highlighted the complexity of their management and led to underline how baseline evaluation and close follow-up with echocardiography and cardiac biomarkers, including natriuretic peptides, remain an important tool for the cardiotoxicity surveillance. Conclusion: These reflections should lead to further studies in order to identify high risk patients for cardiovascular adverse event and clarify the real incidence of cardiotoxicity of this drug and adequate follow-up timing. Finally further research is needed to evaluate strategies for prevention and attenuation of cardiovascular complications of cancer therapy.

Percutaneous Coronary Intervention Does Not Lower Cardiovascular Outcomes in Patients with Chronic Kidney Disease

Background: Chronic kidney disease (CKD) is associated with an increased risk of adverse cardiovascular outcomes, in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). However, most studies used bare-metal stents or first-generation drug-eluting stents, and less guideline-directed therapy to reduce cardiovascular risk was reported in CKD patients. This study investigates the impact of moderate-CKD on patients undergoing PCI in the current era. Methods: Patient level data were pooled from 2 multicenter randomized trials (BIONICS and NIREUS trials) with a near “all-comers” design, comparing PCI with ridaforolimus-eluting stents vs. zotarolimus-eluting stents in patients with CAD. Patients were classified according to the presence or absence of moderate-CKD, defined as creatinine clearance (CrCl) <60 mL/min. We compared baseline characteristics, angiographic findings, and clinical outcomes 1-year post-PCI. Results: 236/2,201 (10.7%) patients had CKD, mean CrCl of 50.3 + 7.8 mL/min. These patients were generally older and more often with hypertension than non-CKD patients, but the use of guideline-directed therapy was similar between the groups. CKD was associated with an increased risk of cardiovascular death (hazard ratio [HR] 6.08; 95% CI 2.11–17.51; p < 0.001), but with a reduced occurrence of repeated revascularization, including ischemia-driven revascularization (HR 0.47; 95% CI 0.24–0.92; p < 0.05). The rate of repeated angiography per severe cardiovascular adverse event was significantly lower in the CKD than the non-CKD group (23/38 [61%] vs. 253/334 [76%], p < 0.05). Conclusions: Moderate-CKD in patients with CAD was associated with higher rates of all-cause and cardiovascular mortality, yet with a lower risk of revascularization 1-year following PCI. Lack of guideline-directed medical therapy does not explain the adverse outcome of CKD patients.

The Effect of Adding Midazolam to Propofol Intravenous Sedation to Suppress Gag Reflex During Dental Treatment

We retrospectively investigated the efficacy and safety of propofol administration alone and in combination with midazolam for gag reflex suppression during dental treatment under intravenous sedation. We included 56 patients with an overactive gag reflex who were to undergo dental treatment under intravenous sedation. They were divided into propofol (P group, n = 22) and midazolam with propofol (MP group, n = 34) groups. The P group received propofol alone, while the MP group received midazolam (0.04 mg/kg) prior to target-controlled infusion (TCI) of propofol (titrated for adequate sedation). The patients' anesthetic records were evaluated for vital sign changes, adverse cardiovascular or respiratory event frequency, the number of forced treatment interruptions, and the TCI-predicted cerebral propofol concentration at gag reflex suppression (posterior tongue stimulation with a dental mirror). No significant differences were observed between the 2 groups preoperatively. There were no cases of forced interruptions or significant respiratory compromise in either group. Cardiovascular adverse event frequency was lower in the MP group than in the P group (all p &lt; .05). Our results suggest that propofol, when combined with midazolam, minimized cardiovascular effects compared with propofol alone when used to suppress the gag reflex in patients during dental treatment under intravenous sedation.