Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer.

Vascular endothelial growth factor (VEGF) has been shown to stimulate angiogenesis and myocardial perfusion. The short-term safety of VEGF gene therapy is excellent. However, there are only limited results regarding the long-term effects. The Kuopio Angiogenesis Trial (KAT) studied the efficiency and short-term safety of the local VEGF-A(165) gene transfer in 103 patients with coronary artery disease. Three patient groups received either VEGF as an adenoviral (n=37), or as a plasmid/liposome vector (n=28), or as a placebo (n=38), during coronary angioplasty and stenting (percutaneous coronary intervention, PCI)AQ1. The aim of this study was to examine the long-term effects and safety of VEGF gene therapy. Patients were interviewed by telephone or with a questionnaire on their current status of health, coronary and other cardiovascular events and symptoms, working ability, exercise tolerance, other diseases, such as cancer and diabetes, as well as their personal experience of the treatment. Causes of death were clarified from hospital records. The total follow-up time was 8.1 years (range 6.9-9.7 years). Overall 82% of the patients were reached across the study. Eight (7.5%) of the patients died during the follow-up, but there was no significant difference in mortality between the groups (3/32 vs 2/26 vs 3/31 VEGF-adenovirus vs VEGF-plasmid/liposome vs placebo, respectively; P=0.88). The incidence of major adverse cardiovascular events (MACEs) (10 vs 11 vs 15; P=0.85), cancer (1 vs 4 vs 2; P=0.38) or diabetes (2 vs 2 vs 2; P=0.97) did not differ between the groups. Local intracoronary VEGF gene transfer is safe and does not increase the risk of MACE, arrhythmias, cancer, diabetes or other diseases.

Mountain birch under multiple stressors--heavy metal-resistant populations co-resistant to biotic stress but maladapted to abiotic stress.

Stress adaptations often include a trade-off of weakened performance in nonlocal conditions, resulting in divergent selection, and potentially, genetic differentiation and evolutionary adaptation. Results of a two-phase (greenhouse and field) common garden experiment demonstrated adaptation of mountain birch (Betula pubescens subsp. czerepanovii) populations from industrially polluted areas of the Kola Peninsula, north-western Russia, to heavy metals (HM), whereas no adaptations to wind or drought stress were detected in populations from wind-exposed sites. HM-adapted seedlings were maladapted to drought but less palatable (co-resistant) to insect herbivores, even under background HM concentrations. The absence of adaptations to harsh microclimate and the generally high adaptive potential of mountain birch, a critical forest forming tree in subarctic Europe, need to be accounted for in models predicting consequences of human-driven environmental changes, including the projected climate change.

Rapid evolution towards heavy metal resistance by mountain birch around two subarctic copper-nickel smelters.

Adaptations to pollution among long-lived trees have rarely been documented, possibly because of their long reproductive cycles and the evolutionarily short timescales of anthropogenic pollution. Here, I present the results of a greenhouse experiment that suggest rapid evolutionary adaptation of mountain birch [Betula pubescens subsp. czerepanovii (Orlova) Hämet-Ahti] to heavy metal (HM) stress around two copper-nickel smelters in NW Russia. The adaptation incurs a cost with reduced performance of adapted seedlings in pristine conditions. The industrial barrens around the studied smelters are extremely high-stress sites with low seed germination and survival. It is likely that strong natural selection has eliminated all sensitive genotypes within one or two generations, with only the most tolerant individuals persisting and producing adapted seeds in the individual barrens. The results were similar from around both smelters, suggesting parallel evolution towards HM resistance.

Anticipatory blood pressure responses to exercise are associated with left ventricular mass in Finnish men: Kuopio Ischemic Heart Disease Risk Factor Study.

BACKGROUND: Exaggerated cardiovascular reactivity to psychological demands may contribute to the development of left ventricular (LV) hypertrophy. We examined the cross-sectional association between anticipatory blood pressure (BP) responses to bicycle exercise and LV mass in the Kuopio Ischemic Heart Disease Risk Factor Study, a population-based epidemiological sample. METHODS AND RESULTS: Among 876 men from 4 age cohorts (ages 42, 48, 58, and 64 years), we collected echocardiographic assessments of LV mass along with measures of BP response taken before bicycle ergometry testing. Anticipatory BP responses were positively associated with LV mass, with significant associations only among younger (age <50 years) subjects with elevated resting pressures (3-way interactions for anticipatory BP x age x resting pressure for systolic and diastolic BP, all P:<0.05; for younger subjects with elevated systolic BP, P:<0. 01; and for younger subjects with elevated diastolic BP, P:<0.001). Among these subgroups, exaggerated anticipatory BP responses (top quartile) were associated with an incremental increase in LV mass of 10% or greater, corrected for body surface area. Results remained significant after adjusting for age, education, salt consumption, and resting BP, and the pattern of findings was maintained among men with no previous history of cardiovascular disease. CONCLUSIONS: The tendency to show exaggerated pressor responses to psychological demands may be a significant independent correlate of LV mass, especially among young men with high resting pressures. This is the first study to examine such associations in a middle-aged population sample.

Exercise-induced silent myocardial ischemia and coronary morbidity and mortality in middle-aged men.

OBJECTIVES: We investigated the prognostic significance of exercise-induced silent myocardial ischemia in both high and low risk men with no prior coronary heart disease (CHD). BACKGROUND: Silent ischemia predicts future coronary events in patients with CHD, but there is little evidence of its prognostic significance in subjects free of CHD. METHODS: We investigated the association of silent ischemia, as defined by ST depression during and after maximal symptom-limited exercise test, with coronary risk in a population-based sample of men with no prior CHD followed for 10 years on average. RESULTS: Silent ischemia during exercise was associated with a 5.9-fold (95% CI 2.3 to 11.8) CHD mortality in smokers, 3.8-fold (95% CI 1.9 to 7.9) in hypercholesterolemic men and 4.7-fold (95% CI 2.4 to 9.1) in hypertensive men adjusting for other risk factors. The respective relative risks (RRs) of any acute coronary event were 3.0 (95% CI 1.7 to 5.1), 1.9 (95% CI 1.2 to 3.1) and 2.2 (95% CI 1.4 to 3.5). These associations were weaker in men without these risk factors. Furthermore, silent ischemia after exercise was a stronger predictor for the risk of acute coronary events and CHD death in smokers and in hypercholesterolemic and hypertensive men than in men without risk factors. CONCLUSIONS: Exercise-induced silent myocardial ischemia was a strong predictor of CHD in men with any conventional risk factor, emphasizing the importance of exercise testing to identify asymptomatic high risk men who could benefit from risk reduction and preventive measures.

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.

Association of exercise-induced, silent ST-segment depression with the risk of stroke and cardiovascular diseases in men.

BACKGROUND AND PURPOSE: There are few if any data on the prognostic importance of silent myocardial ischemia during exercise with regard to the risk of stroke and cardiovascular diseases (CVDs) among asymptomatic men. In this prospective study, we investigated the relation of silent myocardial ischemia and the risk of stroke and CVD death in men with and without conventional risk factors. METHODS: The study sample included 1726 middle-aged men with no history of stroke, coronary heart disease, or atrial fibrillation at baseline. Silent myocardial ischemia was defined as a horizontal or downsloping ST-segment depression (>or=1 mm) during exercise electrocardiography. A total of 86 CVD-related deaths and 78 strokes occurred during an average follow-up of 10 years. RESULTS: Men with silent ischemia during exercise had a 3.5-fold increased risk of CVD death and a 2.2-fold increased risk of stroke compared with men without silent ischemia, after adjusting for conventional risk factors. Silent ischemia during exercise was associated with a 3.8-fold (95% confidence interval [CI], 1.5 to 9.5) increased risk for CVD in smokers, a 3.9-fold (95% CI, 2.1 to 7.3) increased risk in hypercholesterolemic subjects, a 3.6-fold (95% CI, 1.9 to 6.8) increased risk in the hypertensives, and 3.8-fold (95% CI, 2.0 to 7.1) increased risk in overweight men. The respective relative risks for stroke were 3.8 (95% CI, 1.1 to 12.5), 3.5 (95% CI, 1.7 to 7.4), 3.4 (95% CI, 1.6 to 7.1), and 2.9 (95% CI, 1.4 to 6.1). CONCLUSIONS: Exercise-induced silent myocardial ischemia is an important indicator of increased risk of stroke and CVD in men with other risk factors, such as smoking, hypercholesterolemia, hypertension, and being overweight.

Intermittent mitral regurgitation and pulmonary edema after aortic valve replacement.

We report intermittent mitral valve regurgitation with 17 acute pulmonary edemas over a 16-month period after aortic valve replacement due to combined aortic valve disease in a 51-year-old man. The mechanism of mitral regurgitation was explained by the relatively large size of the prosthetic valve which had had to be sutured partly below the aortic annulus. It was suspected to interfere with the closure of the mildly diseased mitral valve when under pressure or subjected to volume loadings of the left ventricle which provoked free mitral regurgitation. There was no recurrence of pulmonary edema in the 50 months following mitral valve replacement.

Variation of phlorotannins among three populations of Fucus vesiculosus as revealed by HPLC and colorimetric quantification.

In ecological studies, phlorotannins have conventionally been quantified as a group with similar functionality. Since this group consists of oligo- and polymers, the quantification of their pooled contents alone may not sufficiently describe the variation of these metabolites. Genetic variation, plastic responses to environment, and the ecological functions of separate phlorotannin oligo- and polymers may differ. Two analyses, i.e., the colorimetric Folin-Ciocalteu assay and a normal-phase high-performance liquid chromatographic (HPLC) method were used to study genetic and environmental variation in phlorotannins of the brown alga Fucus vesiculosus (L.). The colorimetric method provides the total phlorotannin content, the latter a profile of 14 separate traces from the phenolic extract that represent an individual or groups of phlorotannins. We reared the algae that originated from three separate populations in a common garden for 3 months under ambient and enriched-nutrient availability and found that they differed in both their total phlorotannin content and in phlorotannin profiles. Some individual traces of the profiles separated the populations more clearly than the colorimetric assay. Although nutrient enrichment decreased total phlorotannin content, it did not show a significant influence on the phlorotannin profile. This implies that plastic responses of compounds other than phlorotannins may interfere with the determination of total phlorotannins. However, the phlorotannin profile and the total content showed genetic variation among local populations of F. vesiculosus; therefore, phlorotannins may respond to natural selection and evolve both quantitatively and qualitatively.