Antti Hedman

Safety and Feasibility of Catheter-Based Local Intracoronary Vascular Endothelial Growth Factor Gene Transfer in the Prevention of Postangioplasty and In-Stent Restenosis and in the Treatment of Chronic Myocardial Ischemia Phase II Results of the Kuopio Angiogenesis Trial (KAT)

Background—Catheter-based intracoronary vascular endothelial growth factor (VEGF) gene transfer is a potential treatment for coronary heart disease. However, only limited data are available about local VEGF gene transfer given during angioplasty (PTCA) and stenting. Methods and Results—Patients with coronary heart disease (n=103; Canadian Cardiovascular Society class II to III; mean age, 58±6 years) were recruited in this randomized, placebo-controlled, double-blind phase II study. PTCA was performed with standard methods, followed by gene transfer with a perfusion-infusion catheter. Ninety percent of the patients were given stents; 37 patients received VEGF adenovirus (VEGF-Adv, 2×1010 pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 &mgr;g of DNA with 2000 &mgr;L of DOTMA:DOPE [1:1 wt/wt]), and 38 control patients received Ringer’s lactate. Follow-up time was 6 months. Gene transfer to coronary arteries was feasible and well tolerated. The overall clinical restenosis rate was 6%. In quantitative coronary angiography analysis, the minimal lumen diameter and percent of diameter stenosis did not significantly differ between the study groups. However, myocardial perfusion showed a significant improvement in the VEGF-Adv-treated patients after the 6-month follow-up. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups. Conclusions—Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows that (1) intracoronary gene transfer can be performed safely (no major gene transfer-related adverse effects were detected), (2) no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and (3) a significant increase was detected in myocardial perfusion in the VEGF-Adv-treated patients.

Adenoviral Catheter-Mediated Intramyocardial Gene Transfer Using the Mature Form of Vascular Endothelial Growth Factor-D Induces Transmural Angiogenesis in Porcine Heart

Background—It is unclear what is the most efficient vector and growth factor for induction of therapeutic vascular growth in the heart. Furthermore, the histological nature of angiogenesis and potential side effects caused by different vascular endothelial growth factors (VEGFs) in myocardium have not been documented. Methods and Results—Adenoviruses (Ad) at 2 doses (2×1011 and 2×1012 viral particles) or naked plasmids (1 mg) encoding Lac Z control, VEGF-A165, or the mature, soluble form of VEGF-D (VEGF-D&Dgr;N&Dgr;C) were injected intramyocardially with the NOGA catheter system into domestic pigs. AdVEGF-D&Dgr;N&Dgr;C gene transfer (GT) induced a dose-dependent myocardial protein production, as measured by ELISA, resulting in an efficient angiogenic effect 6 days after the injections. Also, AdVEGF-A165 produced high gene transfer efficacy, as demonstrated with immunohistochemistry, leading to prominent angiogenesis effects. Despite the catheter-mediated approach, angiogenesis induced by both AdVEGFs was transmural, with maximal effects in the epicardium. Histologically, strongly enlarged &agr;-smooth muscle actin–positive microvessels involving abundant cell proliferation were found in the transduced regions, whereas microvessel density did not change. Myocardial contrast echocardiography and microspheres showed marked increases in perfusion in the transduced areas. VEGF-D&Dgr;N&Dgr;C but not matrix-bound VEGF-A165 was detected in plasma after adenoviral GT. A modified Miles assay demonstrated myocardial edema resulting in pericardial effusion with the higher AdVEGF doses. All effects returned to baseline by 3 weeks. Naked plasmid–mediated GT did not induce detectable protein production or vascular effects. Conclusions—Like AdVEGF-A165, AdVEGF-D&Dgr;N&Dgr;C GT using the NOGA system produces efficient transmural angiogenesis and increases myocardial perfusion. AdVEGF-D&Dgr;N&Dgr;C could be useful for the induction of therapeutic vascular growth in the heart.

Predicting the risk of atrial fibrillation after coronary artery bypass surgery.

Atrial fibrillation (AF) is the most common arrhythmia, with an incidence of 17–33%, after coronary artery bypass grafting (CABG) and it increases the cost of operative treatment. β‐Blocker therapy reduces markedly the incidence of postoperative AF. The more effective preventive methods, e.g. amiodarone therapy or atrial pacing, are not cost‐effective for all the patients. Thus, identification of patients at high risk of AF after CABG would be helpful. This review summarizes the predictors of postoperative AF and the current methods for risk stratification. In summary, identification of the patients at high risk of postoperative AF remains a challenge. The clinical usefulness of most of the conventional factors, e.g. age or history of AF, is low. Even attempts to build logistic regression models based on the pre‐ and intraoperative variables have failed to provide powerful predictors for postoperative AF after CABG. From the new predictors, the P‐wave duration in signal‐averaged ECG looks promising. Sensitivity and negative predictive value are high, positive predictive value remains low, which limits its usefulness. Contrary, even detailed analysis of standard 12‐lead ECG or measure of heart rate variability has failed to provide useful information for risk stratification. A new method for risk stratification has been developed in our centre. The diagnostic accuracy of high‐rate atrial pacing seems to be sufficient to identify a group of patients to whom prophylactic treatment could be proactively targeted. Further experience is, however, warranted to verify significance of this method in everyday clinical practice.

Adenoviral intramyocardial VEGF-DΔNΔC 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-DΔNΔC gene therapy in patients with refractory angina. Methods and results 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 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-DΔNΔC 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.

Analysis of Heart Rate Variability does not Identify the Patients at Risk of Atrial Fibrillation after Coronary Artery Bypass Grafting

Objective : Analysis of heart rate variability (HRV) is a non-invasive method for assessing cardiac autonomic regulation. This study was designed to investigate whether preoperative short-term HRV analysis could identify the patients at high risk of atrial fibrillation (AF) after coronary artery bypass grafting (CABG). Design : HRV measurement was performed preoperatively for 92 elective CABG patients. Results : Thirty patients had AF postoperatively while 62 remained in sinus rhythm (SR). Logistic regression analysis identified two independent predictors for AF after CABG: increased age with an odds ratio (OR) 1.06 per year and higher body mass index (BMI) with an OR 1.18 per unit. However, no measured parameters of HRV analysis differed significantly between AF and SR groups. Conclusion : The patients at high risk of AF after CABG cannot be identified by preoperative short-term HRV analysis performed during standardized physiological conditions. Advanced age and higher BMI were independent risk factors of AF after CABG in this study.

Baroreflex sensitivity in asymptomatic coronary atherosclerosis

Baroreflex sensitivity (BRS) reflects the effectiveness of cardiac parasympathetic regulation. BRS becomes impaired in stable coronary artery disease (CAD) and after myocardial infarction and carries prognostic information in these patients. Whether impaired BRS is found already in asymptomatic subjects, with subclinical coronary atherosclerosis, has remained elusive.

Physiological Background Underlying Short‐Term Heart Rate Variability

A large number of papers has been published on heart rate variability (HRV) based on the assumption that the specific components of HRV provide specific information about cardiac parasympathetic or sympathetic efferent nerve activity. However, neural control of the cardiorespiratory system is very complex, and the physiological phenomenon underlying HRV in different conditions are far from being fully understood. This review summarizes, in the light of current literature, a series of studies focused on the mechanisms by which fluctuations in neural outflows are transferred into HRV. In the interpretation of HRV analyses, it should be taken into account that: (1) HRV seems to be strongly influenced by the parasympathetic nervous system at all the frequency components; (2) due to sympathovagal interactions, sympathetic outflow is able to reduce the variations generated by vagal modulation also in the high frequency band; and (3) the variations in heart rate reflect fluctuations in the neural activity rather than the mean level of sympathetic or parasympathetic neural activity. Thus, we should be cautious in interpreting a specific component of HRV as a specific marker of sympathetic or parasympathetic cardiac control. Furthermore, due to the complexity of the cardiorespiratory control system, the analysis of short‐term HRV should be performed in well‐controlled conditions, in which the behavior of the autonomic nervous system is well documented.

Mouse ECG findings in aging, with conduction system affecting drugs and in cardiac pathologies: Development and validation of ECG analysis algorithm in mice.

Mouse models are extremely important in studying cardiac pathologies and related electrophysiology, but very few mouse ECG analysis programs are readily available. Therefore, a mouse ECG analysis algorithm was developed and validated. Surface ECG (lead II) was acquired during transthoracic echocardiography from C57Bl/6J mice under isoflurane anesthesia. The effect of aging was studied in young (2–3 months), middle‐aged (14 months) and old (20–24 months) mice. The ECG changes associated with pharmacological interventions and common cardiac pathologies, that is, acute myocardial infarction (AMI) and progressive left ventricular hypertrophy (LVH), were studied. The ECG raw data were analyzed with an in‐house ECG analysis program, modified specially for mouse ECG. Aging led to increases in P‐wave duration, atrioventricular conduction time (PQ interval), and intraventricular conduction time (QRS complex width), while the R‐wave amplitude decreased. In addition, the prevalence of arrhythmias increased during aging. Anticholinergic atropine shortened PQ time, and beta blocker metoprolol and calcium‐channel blocker verapamil increased PQ interval and decreased heart rate. The ECG changes after AMI included early JT elevation, development of Q waves, decreased R‐wave amplitude, and later changes in JT/T segment. In progressive LVH model, QRS complex width was increased at 2 and especially 4 weeks timepoint, and also repolarization abnormalities were seen. Aging, drugs, AMI, and LVH led to similar ECG changes in mice as seen in humans, which could be reliably detected with this new algorithm. The developed method will be very useful for studies on cardiovascular diseases in mice.

Preoperative alterations in correlation properties and complexity of R-R interval dynamics predict the risk of atrial fibrillation after coronary artery bypass grafting in patients with preserved left ventricular function.

Introduction: We evaluated whether there are constant preoperative alterations in nonlinear R–R interval dynamics that associate with the risk of postoperative atrial fibrillation in patients with preserved left ventricular function.

Myocardial 123I-metaiodobenzylguanidine Washout and Heart Rate Variability in Asymptomatic Subjects

Background: Myocardial 123I‐metaiodobenzylguanidine (MIBG) kinetics reflect the integrity and function of cardiac presynaptic sympathetic nerve terminals. Heart rate variability (HRV) is an indicator of cardiac sympatho‐vagal balance. However, the function of cardiac sympathetic nerve terminals as a modulator of HRV in asymptomatic subjects has remained elusive. In addition, the physiological background for different components of HRV is not fully established.