Transcatheter Aortic Valve Implantation in Low-Risk Tricuspid or Bicuspid Aortic Stenosis: The NOTION-2 Trial.

BACKGROUND AND AIMS: Transcatheter aortic valve implantation (TAVI) has become the first choice to treat older patients with severe symptomatic aortic stenosis (AS). This study aimed to compare TAVI with surgery in low-risk patients ≤ 75 years of age, including both tricuspid and bicuspid AS. METHODS: The NOTION-2 trial enrolled and 1:1 randomized low-risk patients aged ≤ 75 years with severe symptomatic AS to TAVI or surgery. The primary endpoint was a composite of all-cause mortality, stroke or rehospitalization (related to the procedure, valve or heart failure) at 12 months. RESULTS: A total of 370 patients were enrolled with a mean age of 71.1 years and a median Society of Thoracic Surgeons risk score of 1.1%. A total of 100 patients had bicuspid AS. The 1-year incidence of the primary endpoint was 10.2% in the TAVI group and 7.1% in the surgery group (absolute risk difference 3.1%; 95% confidence interval [CI], -2.7% to 8.8%; hazard ratio (HR) 1.4, 95% CI: 0.7 to 2.9; p=0.3). Patients with TAVI, when compared to surgery, had lower risk of major bleeding and new-onset atrial fibrillation and higher risk of non-disabling stroke, permanent pacemaker implantation and moderate-or-greater paravalvular regurgitation. The risk of the primary composite endpoint was 8.7% and 8.3% in patients with tricuspid AS (HR 1.0, 95% CI: 0.5 to 2.3) and 14.3% and 3.9% in patients with bicuspid AS (HR 3.8, 95% CI: 0.8 to 18.5) treated with TAVI or surgery, respectively (P for interaction=0.1). CONCLUSIONS: Among low-risk patients aged ≤ 75 years with severe symptomatic AS, the rate of the composite of death, stroke, or rehospitalization at one year was similar between TAVI and surgery. TAVI outcomes in young bicuspid AS patients warrant caution and should be further investigated. (NOTION-2, ClinicalTrials.gov, NCT02825134).

Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: do mitral valve leaflet length, septal thickness, or sex affect the outcome?

This retrospective cohort study aimed to assess whether basal septal wall thickness (BSWT), anterior (AML) and posterior (PML) mitral leaflet length, or sex were associated with remaining left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing alcohol septal ablation (ASA). One hundred fifty-four patients who underwent ASA at the Karolinska University Hospital in Stockholm, Sweden, between 2009 and 2021, were included retrospectively. Anatomical and hemodynamic parameters were collected from invasive catheterization before and during ASA, and from echocardiography (ECHO) examinations before, during, and at 1-year follow-up after ASA. Linear and logistic regression models were used to assess the association between sex, BSWT, AML, PML, and outcome, which was defined as the remaining LVOTO (≥ 30 mmHg) after ASA. The median follow-up was 364 days (interquartile range 334-385 days). BSWT ≥ 23 mm (n = 13, 12%) was associated with remaining LVOTO at follow-up (p = 0.004). Elongated mitral valve leaflet length (either AML or PML) was present in 125 (90%) patients. Elongated AML (> 24 mm) was present in 67 (44%) patients, although AML length was not associated with remaining LVOTO at follow-up. Elongated PML (> 14 mm) was present in 114 (74%) patients and was not associated with remaining LVOTO at follow-up. No significant sex differences were observed regarding the remaining LVOTO. ECHO measurement of BSWT can be effectively used to select patients for successful ASA and identify those patients with a risk of incomplete resolution of LVOTO after ASA.

FFR-Guided Complete or Culprit-Only PCI in Patients with Myocardial Infarction.

BACKGROUND: The benefit of fractional flow reserve (FFR)-guided complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear. METHODS: In this multinational, registry-based, randomized trial, we assigned patients with STEMI or very-high-risk non-STEMI (NSTEMI) and multivessel disease who were undergoing primary percutaneous coronary intervention (PCI) of the culprit lesion to receive either FFR-guided complete revascularization of nonculprit lesions or no further revascularization. The primary outcome was a composite of death from any cause, myocardial infarction, or unplanned revascularization. The two key secondary outcomes were a composite of death from any cause or myocardial infarction and unplanned revascularization. RESULTS: A total of 1542 patients underwent randomization, with 764 assigned to receive FFR-guided complete revascularization and 778 assigned to receive culprit-lesion-only PCI. At a median follow-up of 4.8 years (interquartile range, 4.3 to 5.2), a primary-outcome event had occurred in 145 patients (19.0%) in the complete-revascularization group and in 159 patients (20.4%) in the culprit-lesion-only group (hazard ratio, 0.93; 95% confidence interval [CI], 0.74 to 1.17; P = 0.53). With respect to the secondary outcomes, no apparent between-group differences were observed in the composite of death from any cause or myocardial infarction (hazard ratio, 1.12; 95% CI, 0.87 to 1.44) or unplanned revascularization (hazard ratio, 0.76; 95% CI, 0.56 to 1.04). There were no apparent between-group differences in safety outcomes. CONCLUSIONS: Among patients with STEMI or very-high-risk NSTEMI and multivessel coronary artery disease, FFR-guided complete revascularization was not shown to result in a lower risk of a composite of death from any cause, myocardial infarction, or unplanned revascularization than culprit-lesion-only PCI at 4.8 years. (Funded by the Swedish Research Council and others; FULL REVASC ClinicalTrials.gov number, NCT02862119.).

Characteristics and Outcomes of Patients Receiving a Second Rescue Valve During Transcatheter Aortic Valve Implantation.

Background: Transcatheter aortic valve implantation (TAVI) has become a safe procedure. However, complications occur, including uncommon complications such as valve malposition, which requires the implantation of an additional rescue valve (rescue-AV). The aim was to study the occurrence and outcomes of rescue-AV in a nationwide registry. Methods: The Swedish national TAVI registry was used as the primary data source, where all 6706 TAVI procedures from 2016 to 2021 were retrieved. Nontransfemoral access and planned valve-in-valve were excluded. In total, 79 patients were identified as having had a rescue-AV, and additional detailed data were collected for these patients. This dataset was analyzed for any characteristics that could predispose patients to a rescue-AV. The outcome of patients receiving rescue-AV also was studied. Results: Of the 5948 patients in the study, 1.3% had a rescue-AV. There were few differences between patients receiving 1 valve and rescue-AV patients. For patients receiving a rescue-AV, the 30-day mortality was 15.2% compared to 1.6% in the control group. A poor outcome after rescue-AV was often associated with a second complication; for example, stroke, need for emergency surgery, or heart failure. Among the patients with rescue-AV who survived at least 30 days, landmark analyses showed similar survival rates compared to the control group. Conclusions: Among TAVI patients in a nationwide register, rescue-AV occurred in 1.3% of patients. The 30-day mortality in patients receiving rescue-AV was high, but long-term outcome among 30-day survivors was similar to the control group.

Acute myocardial infarction in a patient with congenitally corrected transposition of the great arteries and complex coronary anatomy-a case report.

Background: Congenitally corrected transposition of the great arteries (ccTGA) is a rare congenital heart anomaly with atrioventricular and ventriculoarterial discordance that is often associated with other cardiac and coronary artery anomalies. Here, we report a case of a patient with ccTGA and non-ST elevation myocardial infarction (NSTEMI) with challenging coronary anatomy that was treated with stress-perfusion cardiac magnetic resonance imaging (spCMR) guided percutaneous coronary intervention (PCI). Case summary: A 46-year-old male smoker with ccTGA, dyslipidaemia, diabetes Type 2 managed with dietary restrictions and a family history of premature myocardial infarction, presented with typical chest pain, elevated cardiac troponin levels and ECG-changes indicative of ischaemia. The patient was diagnosed with NSTEMI and underwent initial urgent coronary angiography (CA) without apparent significant stenosis, although the right coronary artery (RCA) could not be selectively investigated. The patient had coronary anatomy 1R-2LCX according to the Leiden convention, which is the usual anatomy in patients with ccTGA. Despite this, CA was challenging due to the different anatomy compared with individuals with normally positioned great vessels. The patient remained highly symptomatic with chest pain at moderate exertion. To improve identification of the anatomic location and extent of ischaemia, we performed spCMR with adenosine. This revealed a limited septal infarction (likely embolic) in the right ventricle and reversible ischaemia in two inferior right ventricular segments. A second angiography, selectively investigating RCA demonstrated a significant stenosis in the distal RCA that was successfully treated with a drug-eluting stent. Fractional flow reserve (FFR) measurements of the left coronary arteries demonstrated hemodynamically non-significant stenosis. The patient's symptoms resolved, and he remained asymptomatic at one month follow-up. Discussion: This ccTGA patient had multiple risk factors for coronary artery disease and presented with NSTEMI. Diagnosis and treatment were challenging due to complex cardiac anatomy and associated different origins of the coronary arteries. We highlight the importance of careful evaluation of the coronary anatomy and functional testing using for example spCMR and FFR to target the culprit coronary vessel(s) in ccTGA complicated by NSTEMI.

Percutaneous plug-based vascular closure device in 1000 consecutive transfemoral transcatheter aortic valve implantations.

BACKGROUND: Arterial access-site related complications constitute a large proportion of adverse events related to cardiac interventions requiring large-bore devices and have significant implications on morbidity, mortality and hospital cost. AIMS: To evaluate the safety and effectiveness of a novel percutaneous plug-based vascular closure device (VCD) in 1000 consecutive patients undergoing transfemoral transcatheter aortic valve implantation (TAVI). METHODS: A single-center observational study evaluating a plug-based VCD (MANTA, Teleflex/Essential Medical Inc., Malvern, Pennsylvania, USA) in patients undergoing TAVI at the Karolinska University Hospital, Stockholm, Sweden. The primary outcome was VCD-related major vascular complication according to the criteria of the Valve Academic Research Consortium (VARC)-2. RESULTS: From May 2017 to September 2020 a total of 1000 consecutive patients underwent transfemoral TAVI with arterial access-site management using the MANTA VCD. VARC-2 major vascular complications occurred in 42 (4.2%) patients: 17 (1.7%) patients intraoperatively received a covered stent, 17 (1.7%) patients underwent surgical repair during hospital stay, 3 (0.3%) patients underwent vascular surgery after discharge, 3 (0.3%) patients had major bleeding and 2 (0.2%) patients had symptoms of claudication with conservative treatment. No significant differences in major complications were seen between individual interventionists irrespective of experience with the device. A larger sheath outer diameter to femoral artery inner diameter ratio was the only factor associated with a significant increase of VCD-related major vascular complications. CONCLUSION: This largest ever real-world evaluation of MANTA for large-bore arteriotomy closure in transfemoral TAVI patients indicates effective and safe arterial access-site management with low complication rates and short learning curve. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov. Unique identifier: NCT04392492.

Left Ventricular Outflow Tract Obstruction Following Transcatheter Mitral Valve Replacement Resolved by Chordal Rupture.

Transcatheter mitral valve replacement carries a risk of left ventricular outflow tract obstruction associated with mortality. We present a case of left ventricular outflow tract obstruction that resolved spontaneously when chords to the anterior mitral leaflet were found to have ruptured. (Level of Difficulty: Advanced.).

The Full Revasc (Ffr-gUidance for compLete non-cuLprit REVASCularization) Registry-based randomized clinical trial.

BACKGROUND: Complete revascularization in ST elevation myocardial infarction (STEMI) patients with multivessel disease has resulted in reduction in composite clinical endpoints in medium sized trials. Only one trial showed an effect on hard clinical endpoints, but the revascularization procedure was guided by angiographic evaluation of stenosis severity. Consequently, it is not clear how Fractional Flow Reserve (FFR)-guided percutaneous coronary intervention (PCI) affects hard clinical endpoints in STEMI. METHODS AND RESULTS: The Ffr-gUidance for compLete non-cuLprit REVASCularization (FULL REVASC) - is a pragmatic, multicenter, international, registry-based randomized clinical trial designed to evaluate whether a strategy of FFR-guided complete revascularization of non-culprit lesions, reduces the combined primary endpoint of total mortality, non-fatal MI and unplanned revascularization. 1,545 patients were randomized to receive FFR-guided PCI during the index hospitalization or initial conservative management of non-culprit lesions. We found that in angiographically severe non-culprit lesions of 90-99% severity, 1 in 5 of these lesions were re-classified as non-flow limiting by FFR. Considering lesions of intermediate severity (70%-89%), half were re-classified as non-flow limiting by FFR. The study is event driven for an estimated follow-up of at least 2.75 years to detect a 9.9%/year>7.425%/year difference (HR = 0.74 at 80% power (α = .05)) for the combined primary endpoint. CONCLUSION: This large randomized clinical trial is designed and powered to evaluate the effect of complete revascularization with FFR-guided PCI during index hospitalization on total mortality, non-fatal MI and unplanned revascularization following primary PCI in STEMI patients with multivessel disease. Enrollment completed in September 2019 and follow-up is ongoing.

Valve-in-Valve Implantation Using the ACURATE Neo in Degenerated Aortic Bioprostheses: An International Multicenter Analysis.

OBJECTIVES: This study reports an international experience using the transfemoral ACURATE neo transcatheter heart valve (Boston Scientific, Marlborough, Massachusetts) for the treatment of degenerated surgical aortic bioprostheses. BACKGROUND: Transcatheter valve-in-valve procedures have emerged as an alternative to redo surgery. Supra-annular prostheses might be particularly useful in this indication. METHODS: This is an international multicenter analysis including 85 patients from 14 centers in Europe and Canada undergoing an ACURATE neo valve-in-valve procedure from March 2015 to February 2019. RESULTS: Internal diameter of the degenerated bioprosthesis was 20.3 ± 2.1 mm. Prosthesis size S was used in 70 (82%) procedures. The median depth of implantation was 3 mm and the upper crown of the ACURATE neo was positioned above the stent posts of the degenerated bioprosthesis in 54 (64%) and inside in 31 (36%). Mean transvalvular gradient before discharge was significantly lower if the upper crown was above the degenerated bioprosthesis (13.7 ± 5.9 mm Hg vs. 19.5 ± 10.0 mm Hg; p = 0.001). However, a high position of the ACURATE neo resulted in embolization in 1 patient, conversion to open-heart surgery in 1, and need for reintervention due to transcatheter heart valve failure within the first 18 months of follow-up in 4. CONCLUSIONS: This early experience shows that a high implantation of the ACURATE neo with the upper crown above the stent posts of the degenerated bioprosthesis resulted in lower mean transvalvular gradients but a higher rate of malpositioning and early valve degeneration.

Plasma biomarker levels and non-obstructive coronary artery disease determined by coronary computed tomography angiography.

PURPOSE: Coronary computed tomography angiography (CTA) and several circulating biomarkers have prognostic value regarding cardiovascular disease (CVD) events, but their association is incompletely studied. We aimed to investigate whether markers of lipid metabolism, inflammation and kidney function could predict non-obstructive coronary artery disease (CAD) determined by coronary CTA, in a low-to-intermediate-risk group. METHODS: Coronary CTA and laboratory testing were performed for 115 subjects (45-70 years), with low prevalence of CVD risk factors, predominantly low-to-intermediate Framingham risk and normal or mildly reduced kidney function. RESULTS: Forty-nine (43%) had no CAD at coronary CTA, and 66 (57%) had CAD in ≥1 segment (stenosis < 50%). Adiponectin was inversely associated with CAD, and lipoprotein(a) and cystatin C were associated with CAD at coronary CTA. In multivariable logistic regression, cystatin C remained an independent predictor of CAD (OR: 2·50, 95% CI: 1·12-5·59). Cystatin C also correlated to the number of diseased segments (rs  = 0·25, P<0·01). CONCLUSION: Higher plasma levels of cystatin C were associated with non-obstructive CAD at coronary CTA in subjects with low-to-intermediate CVD risk and normal to mildly reduced kidney function.

The obesity paradox: An analysis of pre-procedure weight trajectory on survival outcomes in patients undergoing transcatheter aortic valve implantation.

INTRODUCTION: Increased mortality has been observed in those with cardiovascular diseases who are of normal body mass index (BMI) compared to the overweight and the obese. A similar association has been demonstrated in patients undergoing transcatheter aortic valve (TAVI) implantation. However, it still remains unclear whether low or normal BMI itself is unfavourable or whether this is merely a reflection of cardiac cachexia due to severe aortic stenosis. The hypothesis for the study was that weight change prior to TAVI may be associated with increased mortality following the procedure. SUBJECTS, MATERIALS AND METHODS: Single centre retrospective analysis using the SWEDEHEART registry, national mortality statistics and local hospital database. Body mass index was used as the anthropomorphic measurement and patients grouped by WHO categories and weight change trajectory before and at TAVI. Kaplan-Meier survival was constructed and a Cox proportional hazard model used to evaluate predictors of outcome. RESULTS: Consecutive data on 493 patients with three year follow-up between 2008-2015 were evaluated. Overweight and obese body mass index categories (BMI>25) were associated with improved mortality compared to normal and underweight patients (BMI<25) (log rank p=0.02), hazard ratio of 0.68 (0.50-0.93). Weight loss trajectory was associated with increased mortality compared to stable weight (log rank p=0.01), hazard ratio 1.64 p=0.025. CONCLUSION: The pre-procedural weight trajectory of patients undergoing TAVI is an important predictor of clinical outcome after TAVI. Patients with stable weight trajectories are associated with improved mortality outcome compared to those with decreasing weight.

Retrograde Snare Technique to Overcome Hostile Aortic Arch Anatomy During Transcatheter Aortic Valve Implantation.

Percutaneous valve implantation is a recognized therapy for calcific aortic stenosis in those patients who are inoperable or at high surgical risk. The transfemoral approach is the most frequently used method for device delivery, but a tortuous calcific aorta and the inflexibility of large-caliber endovascular equipment can impede progress or even cause the procedure to be abandoned. Herein, the use of a technique employing a snare to safely overcome device obstruction in the aortic arch of an elderly female patient is described. The technique may be of practical value whenever any large-caliber device is obstructed in the circulation.

Early clinical outcome of aortic transcatheter valve-in-valve implantation in the Nordic countries.

OBJECTIVE: Transcatheter valve-in-valve implantation has emerged as an option, in addition to reoperative surgical aortic valve replacement, to treat failed biologic heart valve substitutes. However, the clinical experience with this approach is still limited. We report the comprehensive experience of transcatheter valve-in-valve implantation in the Nordic countries from May 2008 to January 2012. METHODS: A total of 45 transcatheter aortic valve-in-valve implantations were performed during the study period in 11 centers. The mean age of the patients was 80.6 years (range, 61-91), 26 were male and 19 were female, and the mean EuroSCORE, EuroSCORE II, and Society of Thoracic Surgeons score was 35.4, 16.3, and 14.6, respectively. The type of failure was stenosis and combined in 58% (mean and peak aortic valve gradient, 77 and 45 mm Hg, respectively) and regurgitation in 42% of cases. The SAPIEN/XT (Edwards LifeSciences, Irvine, Calif) and CoreValve (Medtronic Inc, Minneapolis, Minn) system was used in 33 and 12 cases, respectively. The access route was transapical in 25, transfemoral in 17, transaortic in 2, and subclavian in 1 case. The mean follow-up was 14.4 months. The periprocedural and postoperative outcomes were assessed using the Valve Academic Research Consortium criteria. RESULTS: No intraprocedural mortality occurred. The technical success rate was 95.6% (1 second valve implantation, 1 conversion to open surgery). The all-cause 30-day mortality was 4.4% (1 cardiac-related and 1 aspiration pneumonia). The major complications within 30 days included stroke in 2.2%, periprocedural myocardial infarction in 4.4%, and major vascular complication in 2.2% of patients. At 1 month, all but 1 patient had either no or mild paravalvular leakage, with a mean and peak valve gradient of 17 mm Hg (range, 4-38) and 30 mm Hg (range, 7-68), respectively. The mean gradient was greater than 20 mm Hg in 17% of patients and remained unchanged at 12 months. The 1-year survival was 88.1%. CONCLUSIONS: Transcatheter valve-in-valve implantation is widely performed, albeit in small numbers, in most centers in the Nordic countries. The short-term results were excellent in this high-risk patient population, demonstrating a low incidence of device- or procedure-related complications. However, a considerable number of patients were left with suboptimal systolic valve performance with unknown long-term effects, warranting close surveillance after transcatheter valve-in-valve implantation.

Impact on image quality and radiation exposure in coronary CT angiography: 100 kVp versus 120 kVp.

BACKGROUND: The risk of radiation-induced cancer has become a major concern with the increasing use of computed tomography (CT). PURPOSE: To compare image quality and radiation doses when decreasing X-ray tube peak kilovoltage (kVp) from 120 to 100 kVp in patients undergoing coronary CT angiography (CCTA). MATERIAL AND METHODS: Patients referred for evaluation of suspected coronary artery disease (CAD) underwent 64-channel detector CCTA using a tube voltage of either 120 kVp (n = 46) or 100 kVp (n = 82). The individual volume CT dose index (CTDI(vol)) and dose length product (DLP) were recorded and effective radiation dose was estimated on the basis of DLP. Subjective image quality was assessed by two radiologists on per-patient based consensus. Vascular density and image noise were quantified in the left main coronary artery (LMCA) and proximal ascending aorta (AA). Mean density in the adjacent perivascular tissue was also quantified. Contrast-to-noise ratio (CNR) was calculated. Corresponding invasive coronary angiography (ICA) was performed, which constituted the gold standard. RESULTS: Mean values in the 100/120 kVp cohorts regarding CNR in the LMCA were 12.7/16.0 (P<0.0001)) and in the AA 13.2/17.2 (P<0.0001), CTDI(vol) 34.4/57.4 mGy (a 40% reduction, P<0.0001), DLP 578/1125 mGy × cm (P<0.0001), and estimated effective dose 9.6/20.2 mSv (P<0.0001). There was no statistically significant difference in subjective image quality between the two cohorts. The sensitivity to detect significant coronary stenoses was 88% (120 kVp) and 84% (100 kVp) and the specificity was 71% (120 kVp) and 74% (100 kVp), respectively. CONCLUSION: By reduction of tube voltage from 120 to 100 kVp at CCTA, while keeping all other scanning parameters unchanged, the radiation dose to the patient can be almost halved while keeping the diagnostic image quality at a clinically acceptable level.

NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study.

BACKGROUND: The aim of this substudy of the EUROINJECT-ONE double-blind randomized trial was to analyze changes in myocardial perfusion in NOGA-defined regions with intramyocardial injections of plasmid encoding plasmid human (ph)VEGF-A(165) using an elaborated transformation algorithm. METHODS AND RESULTS: After randomization, 80 no-option patients received either active, phVEGF-A165 (n=40), or placebo plasmid (n=40) percutaneously via NOGA-Myostar injections. The injected area (region of interest, ROI) was delineated as a best polygon by connecting of the injection points marked on NOGA polar maps. The ROI was projected onto the baseline and follow-up rest and stress polar maps of the 99m-Tc-sestamibi/tetrofosmin single-photon emission computed tomography scintigraphy calculating the extent and severity (expressed as the mean normalized tracer uptake) of the ROI automatically. The extents of the ROI were similar in the VEGF and placebo groups (19.4+/-4.2% versus 21.5+/-5.4% of entire myocardium). No differences were found between VEGF and placebo groups at baseline with regard to the perfusion defect severity (rest: 69+/-11.7% versus 68.7+/-13.3%; stress: 63+/-13.3% versus 62.6+/-13.6%; and reversibility: 6.0+/-7.7% versus 6.7+/-9.0%). At follow-up, a trend toward improvement in perfusion defect severity at stress was observed in VEGF group as compared with placebo (68.5+/-11.9% versus 62.5+/-13.5%, P=0.072) without reaching normal values. The reversibility of the ROI decreased significantly at follow-up in VEGF group as compared with the placebo group (1.2+/-9.0% versus 7.1+/-9.0%, P=0.016). Twenty-one patients in VEGF and 8 patients in placebo group (P<0.01) exhibited an improvement in tracer uptake during stress, defined as a >or =5% increase in the normalized tracer uptake of the ROI. CONCLUSIONS: Projection of the NOGA-guided injection area onto the single-photon emission computed tomography polar maps permits quantitative evaluation of myocardial perfusion in regions treated with angiogenic substances. Injections of phVEGF A165 plasmid improve, but do not normalize, the stress-induced perfusion abnormalities.

Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial.

OBJECTIVES: In the Euroinject One phase II randomized double-blind trial, therapeutic angiogenesis of percutaneous intramyocardial plasmid gene transfer of vascular endothelial growth factor (phVEGF-A(165)) on myocardial perfusion, left ventricular function, and clinical symptoms was assessed. BACKGROUND: Evidence for safety and treatment efficacy have been presented in phase I therapeutic angiogenesis trials. METHODS: Eighty "no-option" patients with severe stable ischemic heart disease, Canadian Cardiovascular Society functional class 3 to 4, were assigned randomly to receive, via the NOGA-MyoStar system (Cordis Corp., Miami Lakes, Florida), either 0.5 mg of phVEGF-A(165) (n = 40) or placebo plasmid (n = 40) in the myocardial region showing stress-induced myocardial perfusion defects on (99m)Tc sestamibi/tetrofosmin single-photon emission computed tomography. RESULTS: No differences among the groups were recorded at baseline with respect to clinical, perfusion, and wall motion characteristics. After three months, myocardial stress perfusion defects did not differ significantly between the VEGF gene transfer and placebo groups (38 +/- 3% and 44 +/- 2%, respectively). Similarly, semiquantitative analysis of the change in perfusion in the treated region of interest did not differ significantly between the two groups. Compared with placebo, VEGF gene transfer improved the local wall motion disturbances, assessed both by NOGA (p = 0.04) and contrast ventriculography (p = 0.03). Canadian Cardiovascular Society functional class classification of angina pectoris improved significantly in both groups but without difference between the groups. No phVEGF-A(165)-related adverse events were observed; however, NOGA procedure-related adverse events occurred in five patients. CONCLUSIONS: The VEGF gene transfer did not significantly improve stress-induced myocardial perfusion abnormalities compared with placebo; however, improved regional wall motion, as assessed both by NOGA and by ventriculography, may indicate a favorable anti-ischemic effect. This result should encourage more studies within the field. Transient VEGF overexpression seems to be safe.

ANP and BNP but not VEGF are regionally overexpressed in ischemic human myocardium.

Angiogenic gene therapy in angina pectoris has been disappointing so far. Reasons might be that the administered genes already are overexpressed in ischemic myocardium, or that atrial and brain natriuretic peptides (ANP and BNP) are overexpressed, as they have anti-angiogenic effects. Five stable angina pectoris patients without heart failure were studied. Left ventricular biopsies were taken during coronary by-pass surgery from a region with stress-inducible ischemia and from a normal region. Both ANP and BNP but not vascular endothelial growth factor (VEGF) and VEGF-receptor 1 and 2 were overexpressed in ischemic regions compared to non-ischemic regions as measured by real-time PCR. The expression of 15 other angiogenic genes measured by oligonucleotide arrays was not consistently increased in ischemic regions. The overexpression of ANP and BNP suggests an anti-angiogenic effect in ischemic heart disease. The lack of overexpression of angiogenic genes supports the concept of therapeutic overexpression of these genes.