Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy: eight-year follow-up of phase 1 KAT301 study

Backgound/Introduction In phase I KAT301 trial, adenovirus-mediated intramyocardial vascular endothelial growth factor-DΔNΔC (VEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved angina at 1-year follow-up without major safety concerns. Purpose Our objective was to investigate the long-term safety and efficacy of AdVEGF-D GT. A total of 30 patients (24 VEGF-D and 6 randomized and blinded controls) participated in KAT301 trial. Methods The mean follow-up time was 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 events (MACEs) and other predefined endpoints including cancer. Results 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 0.90; 95% confidence interval 0.09–9.32; P=0.95). Mortality and 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). Conclusion(s) 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. FUNDunding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Kuopio University Hospital Heart Center Figure 1. The incidence of MACE Figure 2. CCS class

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.

Hemodynamic evaluation of patients with Moyamoya Angiopathy: comparison of resting-state fMRI to breath-hold fMRI and [15O]water PET

Purpose Patients with Moyamoya Angiopathy (MMA) require hemodynamic evaluation to assess the risk of stroke. Assessment of cerebral blood flow with [15O]water PET and acetazolamide challenge is the diagnostic standard for the evaluation of the cerebral perfusion reserve (CPR). Estimation of the cerebrovascular reactivity (CVR) by use of breath-hold-triggered fMRI (bh-fMRI) as an index of CPR has been proposed as a reliable and more readily available approach. Recent findings suggest the use of resting-state fMRI (rs-fMRI) which requires minimum patient compliance. The aim of this study was to compare rs-fMRI to bh-fMRI and [15O]water PET in patients with MMA. Methods Patients with MMA underwent rs-fMRI and bh-fMRI in the same MRI session. Maps of the CVR gained by both modalities were compared retrospectively by calculating the correlation between the mean CVR of 12 volumes of interest. Additionally, the rs-maps of a subgroup of patients were compared to CPR-maps gained by [15O]water PET. Results The comparison of the rs-maps and the bh-maps of 24 patients revealed a good correlation (Pearson’s r = 0.71 ± 0.13; preoperative patients: Pearson’s r = 0.71 ± 0.17; postoperative patients: Pearson’s r = 0.71 ± 0.11). The comparison of 7 rs-fMRI data sets to the corresponding [15O]water PET data sets also revealed a high level of agreement (Pearson’s r = 0.80 ± 0.19). Conclusion The present analysis indicates that rs-fMRI might be a promising non-invasive method with almost no patient cooperation needed to evaluate the CVR. Further prospective studies are required.

HbA1c Independently Predicts Declined Myocardial Perfusion Reserve Index in Patients With Coronary Microvascular Disease Using Stress Perfusion Cardiac Magnetic Resonance: an Observational Study

Background We investigated whether glycated haemoglobin A1c (HbA1c) could independently predict the decline in the myocardial perfusion reserve index (MPRI) in patients with coronary microvascular disease (CMD) by stress perfusion cardiac magnetic resonance (CMR).Methods From November 2019, 174 patients with ischemic symptoms but without obstructive coronary disease were screened. The MPRI was recorded in 88 patients who underwent stress perfusion CMR detection. Eighty patients with an MPRI of < 2.5 were included in the study. The patients were divided into two groups based on whether their MPRI was greater or less than 1.47. The effects of each index on the MPRI were analysed using bivariate correlation analysis, and the risk factors for CMD were explored using logistic regression analysis.ResultsA total of 80 patients with an MPRI of 1.69±0.79 were included (mean age 54.07 ± 11.06 years; 66.3% male). CMD patients with an MPRI of ≤1.47 were higher than those in the group with an MPRI of >1.47 in age (57.61±9.65 years vs. 51.74±11.41 years), presence of diabetes mellitus (45.5% vs. 21.3%), fasting blood glucose levels [6.33(5.16, 8.01) vs. 5.30(5.15, 6.56)], and HbA1c levels [6.30(5.70, 7.70) vs. 5.80(5.60, 6.50)], (P < 0.05). The MPRI was negatively correlated with HbA1c (r=-0.378, P=0.004). Logistic regression analysis showed that HbA1c (OR=2.336, 95% CI: 1.119-4.876, P=0.024) was an independent risk factor for decreased MPRI in all patients with CMD, especially in patients without diabetes (OR=19.953, 95% CI: 1.743-93.449, P=0.029), but not in patients with diabetes (OR=0.984, 95% CI: 0.265-3.658, P=0.981).ConclusionsHbA1c is an independent predictor of MPRI decline in CMD patients, notably in CMD patients without diabetes, but not for those with diabetes.Trial RegistrationThis clinical trial has been registered in the Chinese clinical Trial Registry with an identifier: ChiCTR1900025810.

Myocardial Perfusion Defects in Hypertrophic Cardiomyopathy Mutation Carriers

Background Impaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype‐positive, left ventricular hypertrophy‐negative). Methods and Results A single center, case‐control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre‐phenotypic features of HCM. Individuals with genotype‐positive, left ventricular hypertrophy‐negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH‐fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype‐positive, left ventricular hypertrophy‐negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m 2 , P =0.03), lower left ventricular end‐systolic volume (21.0±6.9 versus 26.7±6.2 mm/m 2 , P ≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤ 0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P =0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls ( P =0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P =0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P =<0.005; 3.01±0.96 versus 3.47±0.75, P =0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P =0.826). Conclusions Regional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring.

Molecular Mechanisms of Adenosine Stress T1 Mapping

Background: Adenosine stress T1 mapping is an emerging magnetic resonance imaging method to investigate coronary vascular function and myocardial ischemia without application of a contrast agent. Using gene-modified mice and 2 vasodilators, we elucidated and compared the mechanisms of adenosine myocardial perfusion imaging and adenosine T1 mapping. Methods: Wild-type (WT), A 2A AR −/− (adenosine A 2A receptor knockout), A 2B AR −/− (adenosine A 2B receptor knockout), A 3 AR −/− (adenosine A 3 receptor knockout), and eNOS −/− (endothelial nitric oxide synthase knockout) mice underwent rest and stress perfusion magnetic resonance imaging (n=8) and T1 mapping (n=10) using either adenosine, regadenoson (a selective A 2A AR agonist), or saline. Myocardial blood flow and T1 were computed from perfusion imaging and T1 mapping, respectively, at rest and stress to assess myocardial perfusion reserve and T1 reactivity (ΔT1). Changes in heart rate for each stress agent were also calculated. Two-way ANOVA was used to detect differences in each parameter between the different groups of mice. Results: Myocardial perfusion reserve was significantly reduced only in A 2A AR −/− compared to WT mice using adenosine (1.06±0.16 versus 2.03±0.52, P <0.05) and regadenoson (0.98±026 versus 2.13±0.75, P <0.05). In contrast, adenosine ΔT1 was reduced compared with WT mice (3.88±1.58) in both A 2A AR −/− (1.63±1.32, P <0.05) and A 2B AR −/− (1.55±1.35, P <0.05). Furthermore, adenosine ΔT1 was halved in eNOS −/− (1.76±1.46, P <0.05) versus WT mice. Regadenoson ΔT1 was approximately half of adenosine ΔT1 in WT mice (1.97±1.50, P <0.05), and additionally, it was significantly reduced in eNOS −/− mice (−0.22±1.46, P <0.05). Lastly, changes in heart rate was 2× greater using regadenoson versus adenosine in all groups except A 2A AR −/− , where heart rate remained constant. Conclusions: The major findings are that (1) although adenosine myocardial perfusion reserve is mediated through the A 2A receptor, adenosine ΔT1 is mediated through the A 2A and A 2B receptors, (2) adenosine myocardial perfusion reserve is endothelial independent while adenosine ΔT1 is partially endothelial dependent, and (3) ΔT1 mediated through the A 2A receptor is endothelial dependent while ΔT1 mediated through the A 2B receptor is endothelial independent.