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Adenoviral intramyocardial VEGF-D?N?C gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up.

ABSTRACT: Aims:We evaluated for the first time the effects of angiogenic and lymphangiogenic AdVEGF-D?N?C gene therapy in patients with refractory angina. Methods and results:Thirty patients were randomized to AdVEGF-D?N?C (AdVEGF-D) or placebo (control) groups. Electromechanical NOGA mapping and radiowater PET were used to identify hibernating viable myocardium where treatment was targeted. Safety, severity of symptoms, quality of life, lipoprotein(a) [Lp(a)] and routine clinical chemistry were measured. Myocardial perfusion reserve (MPR) was assessed with radiowater PET at baseline and after 3- and 12-months follow-up. Treatment was well tolerated. Myocardial perfusion reserve increased significantly in the treated area in the AdVEGF-D group compared with baseline (1.00?±?0.36) at 3?months (1.31?±?0.46, P?=?0.045) and 12?months (1.44?±?0.48, P?=?0.009) whereas MPR in the reference area tended to decrease (2.05?±?0.69, 1.76?±?0.62, and 1.87?±?0.69; baseline, 3 and 12?months, respectively, P?=?0.551). Myocardial perfusion reserve in the control group showed no significant change from baseline to 3 and 12?months (1.26?±?0.37, 1.57?±?0.55, and 1.48?±?0.48; respectively, P?=?0.690). No major changes were found in clinical chemistry but anti-adenovirus antibodies increased in 54% of the treated patients compared with baseline. AdVEGF-D patients in the highest Lp(a) tertile at baseline showed the best response to therapy (MPR 0.94?±?0.32 and 1.76?±?0.41 baseline and 12?months, respectively, P?=?0.023). Conclusion:AdVEGF-D?N?C gene therapy was safe, feasible, and well tolerated. Myocardial perfusion increased at 1?year in the treated areas with impaired MPR at baseline. Plasma Lp(a) may be a potential biomarker to identify patients that may have the greatest benefit with this therapy.

SUBMITTER: Hartikainen J

PROVIDER: S-EPMC5837555 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up.

Hartikainen Juha J Hassinen Iiro I Hedman Antti A Kivelä Antti A Saraste Antti A Knuuti Juhani J Husso Minna M Mussalo Hanna H Hedman Marja M Rissanen Tuomas T TT Toivanen Pyry P Heikura Tommi T Witztum Joseph L JL Tsimikas Sotirios S Ylä-Herttuala Seppo S

European heart journal 20170901 33

<h4>Aims</h4>We evaluated for the first time the effects of angiogenic and lymphangiogenic AdVEGF-DΔNΔC gene therapy in patients with refractory angina.<h4>Methods and results</h4>Thirty patients were randomized to AdVEGF-DΔNΔC (AdVEGF-D) or placebo (control) groups. Electromechanical NOGA mapping and radiowater PET were used to identify hibernating viable myocardium where treatment was targeted. Safety, severity of symptoms, quality of life, lipoprotein(a) [Lp(a)] and routine clinical chemistry ...[more]

PMID: 28903476

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Project description:RationaleA growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function.ObjectiveEvaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options.Methods and resultsIn this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10(5) or 5×10(5) cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients.ConclusionsPatients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10(5) cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.

Project description:RationaleThe effect of stem/progenitor cells on myocardial perfusion and clinical outcomes in patients with refractory angina remains unclear because studies published to date have been small phase I-II trials.ObjectiveWe performed a meta-analysis of randomized controlled trials to evaluate the effect of cell-based therapy in patients with refractory angina who were ineligible for coronary revascularization.Methods and resultsSeveral data sources were searched from inception to September 2015, which yielded 6 studies. The outcomes pooled were indices of angina (anginal episodes, Canadian Cardiovascular Society angina class, exercise tolerance, and antianginal medications), myocardial perfusion, and clinical end points. We combined the reported clinical outcomes (myocardial infarction, cardiac-related hospitalization, and mortality) into a composite end point (major adverse cardiac events). Mean difference (MD), standardized mean differences, or odds ratio were calculated to assess relevant outcomes. Our analysis shows an improvement in anginal episodes (MD, -7.81; 95% confidence interval [CI], -15.22 to -0.41), use of antianginal medications (standardized MD, -0.59; 95% CI, -1.03 to -0.14), Canadian Cardiovascular Society class (MD, -0.58; 95% CI, -1.00 to -0.16), exercise tolerance (standardized MD, 0.331; 95% CI, 0.08 to 0.55), and myocardial perfusion (standardized MD, -0.49; 95% CI, -0.76 to -0.21) and a decreased risk of major adverse cardiac events (odds ratio, 0.49; 95% CI, 0.25 to 0.98) and arrhythmias (odds ratio, 0.25; 95% CI, 0.06 to 0.98) in cell-treated patients when compared with patients on maximal medical therapy.ConclusionsThe present meta-analysis indicates that cell-based therapies are not only safe but also lead to an improvement in indices of angina, relevant clinical outcomes, and myocardial perfusion in patients with refractory angina. These encouraging results suggest that larger, phase III randomized controlled trials are in order to conclusively determine the effect of stem/progenitor cells in refractory angina.

Project description:BackgroundAdenosine cardiovascular magnetic resonance (CMR) can accurately quantify myocardial perfusion reserve. While regadenoson is increasingly employed due to ease of use, imaging protocols have not been standardized. We sought to determine the optimal regadenoson CMR protocol for quantifying myocardial perfusion reserve index (MPRi) - more specifically, whether regadenoson stress imaging should be performed before or after rest imaging.MethodsTwenty healthy subjects underwent CMR perfusion imaging during resting conditions, during regadenoson-induced hyperemia (0.4 mg), and after 15 min of recovery. In 10/20 subjects, recovery was facilitated with aminophylline (125 mg). Myocardial time-intensity curves were used to obtain left ventricular cavity-normalized myocardial up-slopes. MPRi was calculated in two different ways: as the up-slope ratio of stress to rest (MPRi-rest), and the up-slope ratio of stress to recovery (MPRi-recov).ResultsIn all 20 subjects, MPRi-rest was 1.78 ± 0.60. Recovery up-slope did not return to resting levels, regardless of aminophylline use. Among patients not receiving aminophylline, MPRi-recov was 36 ± 16% lower than MPRi-rest (1.13 ± 0.38 vs. 1.82 ± 0.73, P = 0.001). In the 10 patients whose recovery was facilitated with aminophylline, MPRi-recov was 20 ± 24% lower than MPRi-rest (1.40 ± 0.35 vs. 1.73 ± 0.43, P = 0.04), indicating incomplete reversal. In 3 subjects not receiving aminophylline and 4 subjects receiving aminophylline, up-slope at recovery was greater than at stress, suggesting delayed maximal hyperemia.ConclusionsMPRi measurements from regadenoson CMR are underestimated if recovery perfusion is used as a substitute for resting perfusion, even when recovery is facilitated with aminophylline. True resting images should be used to allow accurate MPRi quantification. The delayed maximal hyperemia observed in some subjects deserves further study.Trial registrationClinicalTrials.gov NCT00871260.

Project description:BackgroundA growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR.MethodsRest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [18F]flurpiridaz in a total of 56 mice (7-8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [18F]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging.ResultsOrchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 ± 1.0 vs. 22.2 ± 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 ± 1.2 vs. 27.3 ± 1.2 % ID/mL, p = 0.896). Accordingly, CFRApp was substantially higher in orchiectomized males (Gx vs. sham, 1.43 ± 0.04 vs. 1.23 ± 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFRApp (r = -0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females.ConclusionOur experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients.

Project description:To assess the safety and efficacy of extracorporeal shockwave myocardial revascularization (ESMR) therapy in treating patients with refractory angina pectoris.A single-arm multicenter prospective trial to assess safety and efficacy of the ESMR therapy in patients with refractory angina (class III/IV angina) was performed. Screening exercise treadmill tests and pharmacological single-photon emission computed tomography (SPECT) were performed for all patients to assess exercise capacity and ischemic burden. Patients were treated with 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy end points were exercise capacity by using treadmill test as well as ischemic burden on pharmacological SPECT at 4 months after the last ESMR treatment. Safety measures included electrocardiography, echocardiography, troponin, creatine kinase, and brain natriuretic peptide testing, and pain questionnaires.Fifteen patients with medically refractory angina and no revascularization options were enrolled. There was a statistically significant mean increase of 122.3±156.9 seconds (38% increase compared with baseline; P=.01) in exercise treadmill time from baseline (319.8±157.2 seconds) to last follow-up after the ESMR treatment (422.1±183.3 seconds). There was no improvement in the summed stress perfusion scores after pharmacologically induced stress SPECT at 4 months after the last ESMR treatment in comparison to that at screening; however, SPECT summed stress score revealed that untreated areas had greater progression in ischemic burden vs treated areas (3.69±6.2 vs 0.31±4.5; P=.03). There was no significant change in the mean summed echo score from baseline to posttreatment (0.4±5.1; P=.70). The ESMR therapy was performed safely without any adverse events in electrocardiography, echocardiography, troponins, creatine kinase, or brain natriuretic peptide. Pain during the ESMR treatment was minimal (a score of 0.5±1.2 to 1.1±1.2 out of 10).In this multicenter feasibility study, ESMR seems to be a safe and efficacious treatment for patients with refractory angina pectoris. However, larger sham-controlled trials will be required to confirm these findings.

Project description:Purpose of reviewAccumulating evidence exists for the value of coronary physiology for clinical decision-making in ischemic heart disease (IHD). The most frequently used pressure-derived index to assess stenosis severity, the fractional flow reserve (FFR), has long been considered the gold standard for this purpose, despite the fact that the FFR assesses solely epicardial stenosis severity and aims to estimate coronary flow impairment in the coronary circulation. The coronary flow reserve (CFR) directly assesses coronary blood flow in the coronary circulation, including both the epicardial coronary artery and the coronary microvasculature, but is nowadays less established than FFR. It is now recognized that both tools may provide insight into the pathophysiological substrate of ischemic heart disease, and that particularly combined FFR and CFR measurements provide a comprehensive insight into the multilevel involvement of IHD. This review discusses the diagnostic and prognostic characteristics, as well as future implications of combined assessment of FFR and CFR pressure and flow measurements as parameters for inducible ischemia.Recent findingsFFR and CFR disagree in up to 40% of all cases, giving rise to fundamental questions regarding the role of FFR in contemporary ischemic heart disease management, and implying a renewed approach in clinical management of these patients using combined coronary pressure and flow measurement to allow appropriate identification of patients at risk for cardiovascular events. This review emphasizes the value of comprehensive coronary physiology measurements in assessing the pathophysiological substrate of IHD, and the importance of acknowledging the broad spectrum of epicardial and microcirculatory involvement in IHD. Increasing interest and large clinical trials are expected to further strengthen the potential of advanced coronary physiology in interventional cardiology, consequently inducing reconsideration of current clinical guidelines.

Dataset Information

Adenoviral intramyocardial VEGF-D?N?C gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up.

Publications

Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up.

Similar Datasets

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