Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting.

Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%-50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [15O]-water positron emission tomography. Seven patients received AZD8601 and four received placebo and were followed for 6 months. There were no deaths or treatment-related serious adverse events and no AZD8601-associated infections, immune reactions, or arrhythmias. Exploratory outcomes indicated potential improvement in LVEF, Kansas City Cardiomyopathy Questionnaire scores, and N-terminal pro-B-type natriuretic peptide levels, but the study is limited in size, and significant efficacy conclusions are not possible from the dataset. Naked mRNA without lipid encapsulation may provide a safe delivery platform for introducing genetic material to cardiac muscle, but further studies are needed to confirm efficacy and safety in a larger patient pool.

Wall Shear Stress Predicts Media Degeneration and Biomechanical Changes in Thoracic Aorta.

Objectives: In thoracic aortic aneurysm (TAA) of the ascending aorta (AA), AA is progressively dilating due to the weakening of the aortic wall. Predicting and preventing aortic dissections and ruptures in TAA continues to be challenging, and more accurate assessment of the AA dilatation, identification of high-risk patients, and timing of repair surgery are required. We investigated whether wall shear stress (WSS) predicts pathological and biomechanical changes in the aortic wall in TAA. Methods: The study included 12 patients with bicuspid (BAV) and 20 patients with the tricuspid aortic valve (TAV). 4D flow magnetic resonance imaging (MRI) was performed a day before aortic replacement surgery. Biomechanical and histological parameters, including assessing of wall strength, media degeneration, elastin, and cell content were analyzed from the resected AA samples. Results: WSSs were greater in the outer curves of the AA compared to the inner curves in all TAA patients. WSSs correlated with media degeneration of the aortic wall (ρ = -0.48, p < 0.01), elastin content (ρ = 0.47, p < 0.01), and aortic wall strength (ρ = -0.49, p = 0.029). Subsequently, the media of the outer curves was thinner, more rigid, and tolerated lower failure strains. Failure values were shown to correlate with smooth muscle cell (SMC) density (ρ = -0.45, p < 0.02), and indicated the more MYH10+ SMCs the lower the strength of the aortic wall structure. More macrophages were detected in patients with severe media degeneration and the areas with lower WSSs. Conclusion: The findings indicate that MRI-derived WSS predicts pathological and biomechanical changes in the aortic wall in patients with TAA and could be used for identification of high-risk patients.

Flow displacement and decreased wall shear stress might be associated with the growth rate of an ascending aortic dilatation.

OBJECTIVES: Our goal was to evaluate whether four-dimensional (4D) flow magnetic resonance imaging (MRI) can predict the growth rate of dilatation of the ascending aorta (AA) in patients with a tricuspid, normally functioning aortic valve. METHODS: In this prospective clinical study, aortic 4D flow MRI was performed at the Kuopio University Hospital on 30 patients diagnosed with AA dilatation (maximum diameter >40 mm) between August 2017 and July 2020. The MRI was repeated after a 1-year follow-up, with AA dimensions and 4D flow parameters analysed retrospectively at both time points. The standard error of measurement was used to assess the statistical significance of the growth rate of AA dilatation. Flow displacement (FD) was transformed to a class-scaled parameter using FD ≥5% as a threshold. RESULTS: Statistically significant growth [median 2.1 mm (1.5-2.2 mm); P = 0.03] was detected in 6 male patients (20%); the AA diameter remained unchanged [0.2 mm (-0.3 to 0.9 mm)] in 24 patients (80%). An increased FD at the baseline was associated with significant growth during the 1-year follow-up in the proximal AA. An association was detected between decreased total wall shear stress and significant aortic growth in the inner curve of the sinotubular junction [529 mPa (449-664 mPa) vs 775 mPa (609-944 mPa); P = 0.03] and the anterior side of the proximal aortic arch [356 mPa (305-367 mPa) vs 493 mPa (390-586 mPa); P < 0.001]. CONCLUSIONS: FD and decreased wall shear stress seem to be associated with significant growth of AA dilatation at the 1-year follow-up. Thus, 4D flow MRI might be useful in assessing risk for AA diameter growth in patients with a tricuspid aortic valve.

Synthetic mRNA Encoding VEGF-A in Patients Undergoing Coronary Artery Bypass Grafting: Design of a Phase 2a Clinical Trial.

Therapeutic angiogenesis may improve outcomes in patients with coronary artery disease undergoing surgical revascularization. Angiogenic factors may promote blood vessel growth and regenerate regions of ischemic but viable myocardium. Previous clinical trials of vascular endothelial growth factor A (VEGF-A) gene therapy with DNA or viral vectors demonstrated safety but not efficacy. AZD8601 is VEGF-A165 mRNA formulated in biocompatible citrate-buffered saline and optimized for high-efficiency VEGF-A expression with minimal innate immune response. EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%-50%) undergoing elective coronary artery bypass surgery. AZD8601 3 mg, 30 mg, or placebo is administered as 30 epicardial injections in a 10-min extension of cardioplegia. Injections are targeted to ischemic but viable myocardial regions in each patient using quantitative 15O-water positron emission tomography (PET) imaging (stress myocardial blood flow < 2.3 mL/g/min; resting myocardial blood flow > 0.6 mL/g/min). Improvement in regional and global myocardial blood flow quantified with 15O-water PET is an exploratory efficacy outcome, together with echocardiographic, clinical, functional, and biomarker measures. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887).

High prevalence of ascending aortic dilatation in a consecutive coronary CT angiography patient population.

OBJECTIVES: To clarify the prevalence and risk factors of ascending aortic (AA) dilatation according to ESC 2014 guidelines. METHODS: This study included 1000 consecutive patients scheduled for diagnostic coronary artery computed tomographic angiography. AA diameter was retrospectively measured in 3 planes: sinus valsalva, sinotubular junction, and tubular part. The threshold for AA dilatation was set to > 40 mm which has been suggested as an upper normal limit for AA diameter in ESC 2014 guidelines on aortic diseases. Aortic size index (ASI) using the ratio between aortic diameter and body surface area (BSA) was applied as a comparative measurement. The threshold for AA dilatation was set to the upper limit of normal distribution exceeding two standard deviations (95%). Risk factors for AA dilatation were collected from medical records. RESULTS: The patients' mean age was 52.9 ± 9.8 years (66.5% women). The prevalence of AA dilatation was 23.0% in the overall study population (52.5% males) and 15.1% in the subgroup of patients with no coronary artery disease or bicuspid (BAV)/mechanical aortic valve (n = 365). According to the normal-distributed ASI values, the threshold for sinus valsalva was defined as 23.2 mm/m2 and for tubular part 22.2 mm/m2 in the subgroup. Higher BSA was associated with larger AA dimensions (r = 0.407, p < 0.001). Male gender (p < 0.001), BAV (p < 0.001), hypertension (p = 0.009) in males, and smoking (p < 0.001) appeared as risk factors for AA dilatation. CONCLUSIONS: The prevalence of AA dilatation is high with current ESC guidelines for normal AA dimension, especially in males. Body size is strongly associated with AA dimensions; it would be more reliable to use BSA-adjusted AA diameters for the definition of AA dilatation. KEY POINTS: • The prevalence of AA dilatation is high in patients who are candidates for coronary CT angiography. • Body size is strongly associated with AA dimensions.

Aortic dilatation associates with flow displacement and increased circumferential wall shear stress in patients without aortic stenosis: A prospective clinical study.

BACKGROUND: The relationship between blood flow characteristics and ascending aortic (AA) dilatation has not been studied in patients with a tricuspid aortic valve (TAV) without aortic stenosis. PURPOSE: To evaluate whether 4D flow characteristics determined in MRI are related to AA dilatation by comparing dilated AA and nondilated AA subjects with TAV. STUDY TYPE: Prospective. POPULATION: Twenty patients with dilated AA and 20 age-matched patients with nondilated AA. FIELD STRENGTH/SEQUENCE: 1.5T/4D flow, 2D flow, and anatomic images. ASSESSMENT: Altogether, 16 different 4D flow parameters were assessed in 10 planes in the thoracic aorta. Intra- and interobserver reproducibility were analyzed. STATISTICAL TESTS: Independent t-test for normally distributed and the Mann-Whitney test for skewed distributed parameters were used. A paired-samples t-test was used to compare 2D and 4D flow parameters. Intraclass correlation coefficient (ICC) was used in intra- and interobserver reproducibility analysis. RESULTS: Aortic flow was displaced from the centerline of the aorta in the proximal and tubular planes. Flow displacement (FD) was greatest in the proximal plane of AA and was higher in dilated AA (4.5%, range 3.0-5.8%) than in nondilated AA (2.0%, 1.0-3.0%, P < 0.001). Total wall shear stress (WSS) values were 1.3 ± 0.4 times higher on the displaced side than on the opposite side of the aorta (P < 0.01). The circumferential WSS (WSSC ) ratio to total WSS was greater in dilated AA, being 0.48 ± 0.11 vs. 0.32 ± 0.09 in the inner curvature of the proximal AA (P < 0.001) and 0.37 ± 0.11 vs. 0.26 ± 0.07 in the whole aortic ring in the distal AA (P < 0.001). Depending on 4D flow parameters, reproducibility varied from excellent (ICC = 0.923) to very low (ICC = 0.204). DATA CONCLUSION: The present study demonstrates that 4D flow measurements help to visualize the pathological flow patterns related to aortic dilatation. Flow displacement and an increased WSSc/WSS ratio are significantly associated with AA dilatation. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:136-145.

Early and midterm outcomes after endovascular treatment of degenerative aneurysms of the descending thoracic aorta: a Finnish multicenter study.

PURPOSE: To evaluate results of endovascular stent-graft placement for aneurysms of the descending aorta in 3 Finnish university hospitals during 1998-2010. METHODS: Among 158 consecutive patients treated with stent-graft placement for disease of the descending thoracic aorta, all 69 patients (58 men; mean age 71.7 years, range 54-90) with an aneurysm were included in the analysis. Medical records, radiological images, and national death records were collected and analyzed on an intention-to-treat basis. RESULTS: The 30-day mortality rate was 3.7% in 54 elective patients and 46.7% in 15 urgently treated acute patients. The paraparesis rate was 4.3%, and the major stroke rate was 4.3% after the operation. There were 4 aneurysm ruptures, all in the urgent group, two of whom had access failure. The other two died despite seemingly good initial results. The mean follow-up was 34.8±29 months. Two late ruptures occurred in patients who were lost to follow-up. In all, 12 type I (10 early, 2 late) and 1 late type III endoleaks were encountered in the observation period. CONCLUSION: Based on our findings, endovascular treatment of aneurysms of the descending aorta is relatively safe. To reduce the risk of postoperative complications, optimal preoperative imaging is mandatory. Postoperative regular imaging controls are indicated for early detection and prompt treatment of late type I or III endoleaks and to reduce the risk of late ruptures.

Right atrial overdrive pacing does not prevent atrial fibrillation after coronary artery bypass surgery.

AIMS: The purpose of this prospective randomized study was to investigate the efficacy of atrial overdrive pacing (AOP) and bradycardia prevention pacing (BPP) in the prophylaxis of atrial fibrillation (AF) after coronary artery bypass surgery (CABG). METHODS: One hundred and twenty-four on-pump CABG patients were randomized into three groups: AOP, BPP, and NP (no pacing). AOP patients were paced via epicardial wires using an atrial preference pacing algorithm, and BPP patients were paced in the AAI mode with a base rate of 60/min. Patients were paced for 48 h starting on the first postoperative day. The endpoint of the study was the first onset of AF lasting longer than 5 min. RESULTS: Preoperative risk factors and surgical data of patients did not differ between the AOP, BPP and NP groups. Pacing was technically successful in 80.5% of patients in the AOP and in 92.7% in the BPP groups. The incidence of AF in the AOP (26.8%), BPP (19.5%) and NP (28.6%) groups did not differ significantly. In the AOP group, AF in three patients was probably induced by inappropriate pacing due to sensing failure. CONCLUSIONS: Atrial overdrive pacing and bradycardia prevention pacing were not effective in the prevention of AF after CABG.

Infrainguinal revascularization because of claudication: total long-term outcome of endovascular and surgical treatment.

OBJECTIVE: This study was undertaken to define total long-term outcome achievable with invasive treatment, ie, endovascular or surgical, in patients with claudication with infrainguinal lesions. Priority in primary treatment was given to percutaneous transluminal angioplasty. METHODS: Data were analyzed for 233 consecutive patients with claudication in whom primary infrainguinal revascularization was performed in 304 limbs between 1989 and 1992. Patients were followed-up to May 2001 (mean, 81 months). Treatment included primary endovascular therapy when applicable (n = 272 limbs) or primary surgical treatment (n = 32; 10.5%). Type of further revascularization, if required, was selected on an individual basis for each patient. All procedures performed because of limb ischemia were recorded. Clinical outcome at the end of follow-up was compared with the preoperative condition. Cumulative primary, secondary, and total patency rates and development of chronic critical ischemia (CCI) were defined. Total patency reflects the ultimate achievable benefit of invasive treatment and refers to patency maintained at the primarily treated segment by means of any invasive (endovascular or surgical) therapy, including potential crossover to another treatment group. RESULTS: A mean of 2 (median, 1) operations per limb were performed during follow-up. No additional operations were needed in 50.3% (n = 153) of limbs. Fontaine classification at the end of the study was better compared with the preoperative value (P <.0005). Crossover between endovascular and surgical treatment was recorded in 21.1% (n = 64) of limbs. At 5 years, primary, secondary, and total patency rates (plus or minus standard error of estimate [SEE]) were 27% +/- 3%, 45% +/- 3%, and 61% +/- 3%, respectively, and at 10 years these rates were 16% +/- 3%, 27% +/- 3%, and 41% +/- 3%. CCI developed in 37 limbs (12.2%), of which 15 (41%) had been treated with endovascular methods only. Type II diabetes and hypertension were statistically significant predictors of increased risk for CCI. CONCLUSION: Combining endovascular and surgical methods when necessary improved total outcome of invasive infrainguinal treatment of claudication. Crossover between endovascular and surgical treatment was required in 21% of limbs over the long term.

Long-term outcome of patients with claudication after balloon angioplasty of the femoropopliteal arteries.

PURPOSE: To report the long-term outcome of patients with lifestyle-limiting claudication after percutaneous transluminal angioplasty (PTA) of the femoropopliteal arteries. MATERIALS AND METHODS: Between 1989 and 1992, 173 consecutive claudicant patients (mean age, 65 years; age range, 41-90 years) underwent PTA in 218 limbs; all interventions included femoral and/or popliteal arterial segments, and additional iliac (n = 27) and infrapopliteal (n = 11) arterial lesions were also treated. Patients were followed up for 7-10 years. Altogether, 37 (17%) limbs were classified as Fontaine class 2A, and 181 (83%) were class 2B. Average length of the primary lesion was 5.2 cm. Reinterventions were analyzed. Patency rates and patient survival were assessed by means of life table analysis. Cox-Mantel tests and Cox proportional hazards models were used to define associated independent determinants. Development of chronic critical ischemia (CCI) and its determinants was assessed by using the Pearson chi(2) test and multiple logistic regression analysis. RESULTS: The primary and secondary patencies (+/- standard error of the estimate), respectively, were 46% +/- 3 and 63% +/- 3 at 1 year, 25% +/- 3 and 41% +/- 4 at 5 years, and 14% +/- 3 and 22% +/- 4 at 10 years. One-third (71 of 218) of the limbs required repeat interventions, including surgical revascularization in 35 limbs. Fourteen (6.4%) limbs developed CCI, resulting in a 0.8% incidence per year. In multivariate analysis, poor postinterventional peripheral runoff was an indicator of increased risk of CCI development (P =.03). CONCLUSION: Although the long-term patency rates of PTA of the femoropopliteal arteries in claudicant patients were poor, the acceptable number of reinterventions and the low frequency of development of CCI imply the long-term benefits achievable with this treatment.

Failure of prolonged dilation to improve long-term patency of femoropopliteal artery angioplasty: results of a prospective trial.

PURPOSE: To determine long-term patency of femoropopliteal artery percutaneous transluminal angioplasty (PTA) in a prospective trial during which prolonged balloon inflation was used for optimization of initial results. MATERIALS AND METHODS: Femoropopliteal PTA was performed in 112 limbs of 97 patients. The mean total length of the treated segments was 7.2 cm (95% CI: 5.99-8.46; median: 5.5 cm). In cases of unsatisfactory primary results after standard dilation for 1-3 minutes, the procedure was continued with prolonged dilation (93 limbs; mean balloon inflation time: 31 min; 95% CI: 24.2-37.7; median: 15 min) with use of the same balloon catheter (77 limbs) or a perfusion balloon catheter (35 limbs). Thirty-four proximal infrapopliteal artery stenoses were treated to improve peripheral runoff and 12 short stents were placed because of flow-limiting dissections. RESULTS: Primary hemodynamic success established by Doppler ultrasound (US) criteria was achieved in 92.9% (104 of 112) of the limbs. Three major complications were encountered; none were related to prolonged balloon inflation. The primary patency rate according to Kaplan-Meier analysis was 42% (+/-5% SE) at 1 year and 39% (+/-5%) at 2 and 3 years. The corresponding secondary patency rates were 51% (+/-5%) and 47% (+/-5%). Large numbers of diseased vessels in the treated limb (four to 10 instead of one to three), eccentric lesions (as opposed to concentric morphology), and additional treated segments (instead of only femoropopliteal lesions) were associated with poorer long-term patency. The duration of balloon dilation was not a determinant of long-term patency. CONCLUSION: Although prolonged dilation is safe and feasible in femoropopliteal artery PTA, its routine use is not warranted because it does not result in superior long-term patency rates.