Juha Hartikainen

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.

Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation.

BACKGROUND There are limited data comparing radiofrequency catheter ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation. METHODS We randomly assigned 294 patients with paroxysmal atrial fibrillation and no history of antiarrhythmic drug use to an initial treatment strategy of either radiofrequency catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up included 7-day Holter-monitor recording at 3, 6, 12, 18, and 24 months. Primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation on Holter-monitor recordings). Analyses were performed on an intention-to-treat basis. RESULTS There was no significant difference between the ablation and drug-therapy groups in the cumulative burden of atrial fibrillation (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group than in the drug-therapy group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any atrial fibrillation (85% vs. 71%, P=0.004) and from symptomatic atrial fibrillation (93% vs. 84%, P=0.01). One death in the ablation group was due to a procedure-related stroke; there were three cases of cardiac tamponade in the ablation group. In the drug-therapy group, 54 patients (36%) underwent supplementary ablation. CONCLUSIONS In comparing radiofrequency ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation, we found no significant difference between the treatment groups in the cumulative burden of atrial fibrillation over a period of 2 years. (Funded by the Danish Heart Foundation and others; MANTRA-PAF ClinicalTrials.gov number, NCT00133211.).

Catheter-Mediated Vascular Endothelial Growth Factor Gene Transfer to Human Coronary Arteries after Angioplasty

Blood vessels are among the easiest targets for gene therapy. However, no data are available about the safety and feasibility of intracoronary gene transfer in humans. We studied the safety and efficacy of catheter-mediated vascular endothelial growth factor (VEGF) plasmid/liposome (P/L) gene transfer in human coronary arteries after percutaneous translumenal coronary angioplasty (PTCA) in a randomized, double-blinded, placebo-controlled study. The optimized angioplasty/gene delivery method was previously shown to lead to detectable VEGF gene expression in human peripheral arteries as analyzed from amputated leg samples. Gene transfer to coronary arteries was done with a perfusion-infusion catheter, using 1000 microg of VEGF or beta-galactosidase plasmid complexed with 1000 microl of DOTMA:DOPE liposomes. Ten patients received VEGF P/L, three patients received beta-galactosidase P/L, and two patients received Ringer lactate. Gene transfer to coronary arteries was feasible and well tolerated. Except for a slight increase in serum C-reative protein in all study groups, no adverse effects or abnormalities in laboratory parameters were detected. No VEGF plasmid or recombinant VEGF protein was present in the systemic circulation after the gene transfer. In control angiography 6 months later, no differences were detected in the degree of coronary stenosis between treatment and control groups. We conclude that catheter-mediated intracoronary gene transfer performed after angioplasty is safe and well tolerated and potentially applicable for the prevention of restenosis and myocardial ischemia.

Complications related to permanent pacemaker therapy.

This study evaluates complications related to permanent endocardial pacing in the era of modern pacemaker therapy. There is only limited information available about the complications related to modern cardiac pacing. Most of the existing data are based on the 1970s and are no longer valid for current practice. The recent reports on pacemaker complications are focused on some specific complication or are restricted to early complications. Thus, there are no reports available providing a comprehensive view of complications related to modern cardiac pacing. Four hundred forty‐six patients, who received permanent endocardial pacemakers between January 1990 and December 1995 at Kuopio University Hospital, were reviewed retrospectively using patient records. Attention was paid to the occurrence of any complication during the implantation or follow‐up. An early complication was detected in 6.7%, and 4.9% of patients were treated invasively due to the early complication. Late complication developed in 7.2% and reoperation was required in 6.3% of the patients. Complications related to the implantation procedure occurred in 3.1%. Inadequate capture or sensing was observed in 7.4% of the patients. Pacemaker infection was detected in 1.8% and erosion in 0.9% of the patients. An AV block developed in 3.6% (1.6%/year) patients who received an AAI(R)‐pacemaker due to sick sinus syndrome. There was no mortality attributable to pacemaker therapy. A great majority (68%) of the complications occurred within the first 3 months after the implantation. Complications associated to modern permanent endocardial pacemaker therapy are not in‐frequent.Elevan percent of patients needed an invasive procedure due to an early or late complication.

Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction †

Aims To determine whether risk stratification tests can predict serious arrhythmic events after acute myocardial infarction (AMI) in patients with reduced left ventricular ejection fraction (LVEF ≤ 0.40). Methods and results A total of 5869 consecutive patients were screened in 10 European centres, and 312 patients (age 65 ± 11 years) with a mean LVEF of 31 ± 6% were included in the study. Heart rate variability/turbulence, ambient arrhythmias, signal-averaged electrocardiogram (SAECG), T-wave alternans, and programmed electrical stimulation (PES) were performed 6 weeks after AMI. The primary endpoint was ECG-documented ventricular fibrillation or symptomatic sustained ventricular tachycardia (VT). To document these arrhythmic events, the patients received an implantable ECG loop-recorder. There were 25 primary endpoints (8.0%) during the follow-up of 2 years. The strongest predictors of primary endpoint were measures of heart rate variability, e.g. hazard ratio (HR) for reduced very-low frequency component (<5.7 ln ms2) adjusted for clinical variables was 7.0 (95% CI: 2.4–20.3, P < 0.001). Induction of sustained monomorphic VT during PES (adjusted HR = 4.8, 95% CI, 1.7–13.4, P = 0.003) also predicted the primary endpoint. Conclusion Fatal or near-fatal arrhythmias can be predicted by many risk stratification methods, especially by heart rate variability, in patients with reduced LVEF after AMI.

Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial

BACKGROUND Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. METHODS In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. FINDINGS Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 29% for PCI (121 events) and 19% for CABG (81 events), HR 1·48 (95% CI 1·11-1·96), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0066). As-treated estimates were 28% versus 19% (1·55, 1·18-2·04, p=0·0015). Comparing PCI with CABG, 5 year estimates were 12% versus 9% (1·07, 0·67-1·72, p=0·77) for all-cause mortality, 7% versus 2% (2·88, 1·40-5·90, p=0·0040) for non-procedural myocardial infarction, 16% versus 10% (1·50, 1·04-2·17, p=0·032) for any revascularisation, and 5% versus 2% (2·25, 0·93-5·48, p=0·073) for stroke. INTERPRETATION The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease. FUNDING Biosensors, Aarhus University Hospital, and participating sites.

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.

Sympathovagal balance is major determinant of short-term blood pressure variability in healthy subjects

Short-term blood pressure variability (BPV) has been suggested to provide important information about cardiovascular regulation. However, the background of BPV, its determinants, and physiological correlates have remained obscure. The aim of this study was to characterize physiological correlates of BPV and to investigate associations between BPV and neural and hormonal regulatory systems at rest in healthy subjects. We studied 117 healthy, normal-weight, nonsmoking male and female subjects aged 23-77 yr. Spectral analysis of BPV and heart rate variability (HRV) was performed from 5-min blood pressure (Finapres) and electrocardiogram recordings during controlled breathing. Baroreflex sensitivity (BRS) was measured using the phenylephrine method. In addition, plasma concentrations of norepinephrine, epinephrine, and arginine vasopressin and plasma renin activity were measured. We found that the ratio between the low- and high-frequency components of HRV, an index of cardiac sympathovagal balance, correlated positively with total power and very low- and low-frequency components of systolic and diastolic BPV and inversely with high-frequency components of systolic and diastolic BPV. BRS, predominantly a measure of cardiac vagal regulation, correlated inversely with BPV. Furthermore, age, gender, body mass index, and systolic blood pressure contributed to BPV. Vasoactive hormones were not significant correlates of BPV. We conclude that sympathovagal balance of cardiovascular regulation is the major determinant of BPV. Other factors associated with BPV are age, gender, body mass index, blood pressure, and BRS.Short-term blood pressure variability (BPV) has been suggested to provide important information about cardiovascular regulation. However, the background of BPV, its determinants, and physiological correlates have remained obscure. The aim of this study was to characterize physiological correlates of BPV and to investigate associations between BPV and neural and hormonal regulatory systems at rest in healthy subjects. We studied 117 healthy, normal-weight, nonsmoking male and female subjects aged 23-77 yr. Spectral analysis of BPV and heart rate variability (HRV) was performed from 5-min blood pressure (Finapres) and electrocardiogram recordings during controlled breathing. Baroreflex sensitivity (BRS) was measured using the phenylephrine method. In addition, plasma concentrations of norepinephrine, epinephrine, and arginine vasopressin and plasma renin activity were measured. We found that the ratio between the low- and high-frequency components of HRV, an index of cardiac sympathovagal balance, correlated positively with total power and very low- and low-frequency components of systolic and diastolic BPV and inversely with high-frequency components of systolic and diastolic BPV. BRS, predominantly a measure of cardiac vagal regulation, correlated inversely with BPV. Furthermore, age, gender, body mass index, and systolic blood pressure contributed to BPV. Vasoactive hormones were not significant correlates of BPV. We conclude that sympathovagal balance of cardiovascular regulation is the major determinant of BPV. Other factors associated with BPV are age, gender, body mass index, blood pressure, and BRS.

Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study.

OBJECTIVES This study sought to explore the incidence and risk factors of thromboembolic complications after cardioversion of acute atrial fibrillation. BACKGROUND Anticoagulation therapy is currently recommended after cardioversion of acute atrial fibrillation in patients with risk factors for stroke, but the implementation of these new consensus-based guidelines has been slow. METHODS A total of 7,660 cardioversions were performed in 3,143 consecutive patients with atrial fibrillation lasting <48 h in 3 hospitals. For this analysis, embolic complications were evaluated during the 30 days after 5,116 successful cardioversions in 2,481 patients with neither oral anticoagulation nor peri-procedural heparin therapy. RESULTS There were 38 (0.7%; 95% confidence interval [CI]: 0.5% to 1.0%) definite thromboembolic events (31 strokes) within 30 days (median 2 days, mean 4.6 days) after cardioversion. In addition, 4 patients suffered transient ischemic attack after cardioversion. Age (odds ratio [OR]: 1.05; 95% CI: 1.02 to 1.08), female sex (OR: 2.1; 95% CI: 1.1 to 4.0), heart failure (OR: 2.9; 95% CI: 1.1 to 7.2), and diabetes (OR: 2.3; 95% CI: 1.1 to 4.9) were the independent predictors of definite embolic events. Classification tree analysis showed that the highest risk of thromboembolism (9.8%) was observed among patients with heart failure and diabetes, whereas patients with no heart failure and age <60 years had the lowest risk of thromboembolism (0.2%). CONCLUSIONS The incidence of post-cardioversion thromboembolic complications is high in certain subgroups of patients when no anticoagulation is used after cardioversion of acute atrial fibrillation. (Safety of Cardioversion of Acute Atrial Fibrillation [FinCV]; NCT01380574).

Natriuretic peptides as markers of cardiotoxicity during doxorubicin treatment for non-Hodgkin's lymphoma

Abstract:  Thirty adult patients with non‐Hodgkins lymphoma who were planned to receive up to 8–10 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) to a cumulative doxorubicin dose of 400–500 mg/m2 were studied to evaluate the value of serial plasma atrial natriuretic peptide (ANP), N‐terminal pro‐ANP (NT‐proANP) and brain natriuretic peptide (BNP) measurements in the early detection of doxorubicin‐induced left ventricular dysfunction. Plasma levels of natriuretic peptides were measured before every treatment course and 4 wk after the last one. Cardiac function was monitored with serial radionuclide ventriculography. Twenty‐eight patients were evaluable for cardiotoxicity. Clinical heart failure developed in 2 patients (7%). Left ventricular ejection fraction (LVEF) decreased from 58.0 ± 1.3% to 49.6 ± 1.7% (p<0.001). Plasma levels of ANP increased from 16.4 ± 1.3 pmol/l to 22.7 ± 2.4 pmol/l (p = 0.002), NT‐proANP from 288 ± 22 to 380 ± 42 pmol/l (p = 0.019) and BNP from 3.3 ±0.4 to 8.5 ± 2.0 pmol/l (p =0.020). There was a significant correlation between the increase in plasma ANP and the decrease in LVEF (r = ‐0.447, p = 0.029), and a trend towards significance between the increase in NT‐proANP and the decrease in LVEF (r=‐0.390, p = 0.059). The decrease in LVEF started very early and could already be seen after the cumulative doxorubicin dose of 200 mg/m2, whereas the increase in plasma natriuretic peptides was not evident until the cumulative doxorubicin dose of 400 mg/m2. Our results show that neuroendocrine activation — increased concentrations of plasma natriuretic peptides — occurs when left ventricular function has reduced substantially and its compensatory capacity has been exceeded resulting in atrial and ventricular overload. Thus, serial natriuretic peptide measurements cannot be used in predicting the impairment of left ventricular function. On the other hand, our study suggests that natriuretic peptides are useful in the detection of subclinical left ventricular dysfunction in patients receiving doxorubicin therapy.