Intramyocardial adenoviral vascular endothelial growth factor-D∆N∆C gene therapy does not induce ventricular arrhythmias.

BACKGROUND: The phase I KAT301 trial investigated the use of intramyocardial adenoviral vascular endothelial growth factor-DΔNΔC (AdVEGF-D) gene therapy (GT) to alleviate symptoms in refractory angina (RA) patients. In KAT301, 30 patients with RA were randomized to AdVEGF-D or the control group in 4:1 ratio. The treatment was found to be feasible, increasing myocardial perfusion and reducing angina symptoms at 1-year follow-up. However, there is some evidence suggesting that the intramyocardial delivery route and overexpression of (vascular endothelial growth) VEGFs might induce ventricular arrhythmias. Thus, we investigated whether intramyocardial AdVEGF-D GT increases the risk of ventricular arrhythmias in patients treated for RA. METHODS: We analyzed non-invasive risk predictors of ventricular arrhythmias from 12-lead electrocardiography (ECG) as well as heart rate variability (HRV) and the incidence of arrhythmias from 24 h ambulatory ECG at baseline and 3 and 12 months after the GT. In addition, we analyzed the incidence of new-onset arrhythmias and pacemaker implantations during 8.2 years (range 6.3-10.4 years) of follow-up. RESULTS: We found no significant increase in arrhythmias, including supraventricular and ventricular ectopic beats, atrial fibrillation, non-sustained ventricular tachycardias, and life-threatening tachycardias, nor changes in the non-invasive risk predictors of ventricular arrhythmias in the AdVEGF-D treated patients. Instead, we found a significant improvement in the very low and high-frequency bands of HRV suggestive of improved cardiac autonomic regulation after GT. CONCLUSIONS: In conclusion, our results suggest that AdVEGF-D GT does not predispose to arrhythmias and might improve HRV metrics.

Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up.

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.

Severe Obstructive Sleep Apnea and Increased Cortical Amyloid-ß Deposition.

BACKGROUND: The suggested association between severe obstructive sleep apnea (OSA) and risk of Alzheimer's disease (AD) needs further study. Only few recent reports exist on associations between brain amyloid-ß (Aß) burden and severe OSA in middle-aged patients. OBJECTIVE: Examine the possible presence of cortical Aß accumulation in middle-aged patients with severe OSA. METHODS: We performed detailed multimodal neuroimaging in 19 cognitive intact patients (mean 44.2 years) with severe OSA (Apnea-Hypopnea Index >30 h-1). Known etiological factors for possible Aß accumulation were used as exclusion criteria. Aß uptake was studied with [11C]-PiB-PET, glucose metabolism with [18F]-FDG-PET, and structural imaging with 3.0T MRI. RESULTS: When analyzed individually, in [11C]-PiB-PET a substantial number (∼32%) of the patients exhibited statistically significant evidence of increased cortical Aß uptake based on elevated regional Z-score values, mostly seen bilaterally in the precuneus and posterior cingulum regions. Cortical glucose hypometabolism in [18F]-FDG-PET was seen in two patients. MRI did not show structural changes suggestive of AD-related pathology. CONCLUSION: Increased [11C]-PiB uptake was seen in middle-aged cognitively intact patients with severe OSA. These findings are similar to those described in cognitive unimpaired older OSA patients. The changes in cortical Aß uptake suggest that severe OSA itself may predispose to alterations related to AD already in middle-age. Aß clearance may be compromised without simultaneous evidence of metabolic or structural alterations. The results emphasize the importance of early diagnostics and proper treatment of severe OSA in cognitively intact middle-aged subjects, possibly diminishing the individual risk for later cognitive dysfunction.

The effect of fatty or lean fish intake on inflammatory gene expression in peripheral blood mononuclear cells of patients with coronary heart disease.

BACKGROUND: Little is known about the effect of fish consumption on gene expression of inflammation-related genes in immune cells in coronary heart disease (CHD). AIM OF THE STUDY: We sought to evaluate the effect of a fatty fish (FF) or a lean fish (LF) diet on the modulation of inflammatory and endothelial function-related genes in peripheral blood mononuclear cells (PBMCs) of subjects with CHD, and its association with serum fatty acid (FA) profile and lipid metabolic compounds. METHODS: Data from 27 patients randomized into an 8-week FF (n = 10; mean +/- SD: 4.3 +/- 0.4 portions of fish per week), LF (n = 11; 4.7 +/- 1.1 portions of fish per week), or control diet (n = 6; 0.6 +/- 0.4 portions of fish per week) were analyzed. The mRNA expression was measured using real-time PCR. RESULTS: The effect of the intervention on the mRNA expression of the genes studied did not differ among groups. In the FF group, however, the decrease in arachidonic acid to eicosapentaenoic acid (AA:EPA) ratio in cholesterol ester and phospholipid fractions strongly correlated with the change in IL1B mRNA levels (r (s) = 0.60, P = 0.06 and r (s) = 0.86, P = 0.002, respectively). In the LF group, the decrease in palmitic acid and total saturated FAs in cholesterol esters correlated with the change in intercellular cell adhesion molecule-1 (ICAM1) expression (r (s) = 0.64, P = 0.04 for both). Circulating levels of soluble ICAM-1 decreased only in the LF group (P < 0.05). CONCLUSIONS: The intake of FF or LF diet did not alter the expression of inflammatory and endothelial function-related genes in PBMCs of patients with CHD. However, the decrease in AA:EPA ratio in serum lipids in the FF group may induce an anti-inflammatory response at mRNA levels in PBMCs. A LF diet might benefit endothelial function, possibly mediated by the changes in serum FA composition.

Effects of fatty and lean fish intake on blood pressure in subjects with coronary heart disease using multiple medications.

BACKGROUND: Intake of fish and long-chain n-3 fatty acids has been of wide interest due to their beneficial effects on cardiovascular risk factors and lower coronary heart disease (CHD) risk. AIM OF THE STUDY: The aim of this pilot study was to examine the effects of fatty fish and lean (white) fish on fatty acid composition of serum lipids and cardiovascular risk factors in subjects with CHD using multiple drugs for this condition. METHODS: The study was an 8-week controlled, parallel intervention. Inclusion criteria were myocardial infarction or unstable ischemic attack, age under 70 years, use of betablockers and presence of sinus rhythm. The subjects were randomized to one of the following groups: 4 meals/week fatty fish (n = 11), 4 meals/week lean fish (n = 12) and control diet including lean meat (n = 10). RESULTS: The mean (+/-SD) of reported fish meals per week was 4.3 +/- 0.4, 4.7 +/- 1.1 and 0.6 +/- 0.4 in the groups, respectively. The proportions of eicosapentaenoic and docosahexaenoic acids in serum lipids increased in the fatty fish group only (P < 0.05). Systolic and diastolic blood pressure levels decreased in the lean fish group (0 vs. 8 week: 3.5 +/- 3.2 and 4.6 +/- 3.6%, respectively, P < 0.05). Serum total triglyceride concentration did not significantly change. HDL cholesterol concentration change differed among groups but without significant post hoc differences. Apolipoprotein A-1 concentration decreased in the control group (0 vs. 8 week, P < 0.05). Coagulation factors, 25-hydroxy vitamin D, and heart rate variability (24 h Holter) did not change among the groups. CONCLUSIONS: Our results suggest that intake of lean fish at least four times per week could reduce blood pressure levels in CHD patients.

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, 2x10(10) pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 microg of DNA with 2000 microL 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.

Elevated midbrain serotonin transporter availability in mixed mania: a case report.

BACKGROUND: Results obtained from brain imaging studies indicate that serotonin transporter (SERT) and dopamine transporter (DAT) densities are altered in major depression. However, no such studies have been published on current mania or hypomania. CASE PRESENTATION: In this single photon emission computed tomography (SPECT) study with [123I]nor-beta-CIT we present a case with simultaneous symptoms of major depression and hypomania. She had an elevated serotonin transporter availability (SERT) in the midbrain and elevated dopamine transporter availability (DAT) in the striatum, which normalised in a one-year follow-up period during which she received eight months of psychodynamic psychotherapy. CONCLUSIONS: To our knowledge, this is the first report on SERT and DAT associated with mania. In our case the availability of both SERT in the midbrain and DAT in the striatum were elevated at baseline and declined during psychotherapy, while the SERT and DAT of the depressed controls increased during psychotherapy. Symptoms of hypomania in the case were alleviated during psychotherapy. Clinical recovery was also reflected in the Hamilton Depression Rating Scale (HDRS) scores.

Half-time myocardial perfusion SPECT imaging with attenuation and Monte Carlo-based scatter correction.

PURPOSE: To test the potential of a new reconstruction algorithm with Monte Carlo-based scatter correction in half-time myocardial perfusion single-photon emission computed tomography (SPECT). MATERIALS AND METHODS: The mathematical four-dimensional NURBS-based Cardiac-Torso phantom and the SIMIND Monte Carlo simulation package were used to simulate full-time and half-time SPECT projection data. The data were reconstructed using the standard ordered subset expectation maximization-based algorithm and the new Monte Carlo-based algorithm. Defect contrast, myocardium versus ventricle contrast and resolution were calculated. In addition to the simulation studies, full-time and half-time SPECT projection data of 30 patients were reconstructed with the standard and the new method. The patient data were qualitatively evaluated by four nuclear medicine experts on a scale from 1 (poor quality) to 5 (high quality). RESULTS: The new reconstruction method with half-time data produced higher contrast and better resolution in the simulations and also achieved higher qualitative scores in the patient study than the standard reconstruction with full-time data. CONCLUSION: Half-time myocardial perfusion imaging using the new reconstruction algorithm with Monte Carlo-based scatter correction produced images with superior quality when compared with full-time imaging with standard reconstruction.

Late potentials and QT dispersion after high-dose chemotherapy in patients with non-Hodgkin lymphoma.

The most common cardiotoxic effects of high-dose cyclophosphamide (CY) are electrocardiographic changes and transient arrhythmias. Therefore, we prospectively assessed serial electrocardiogram (ECG) and signal-averaged electrocardiogram (SAECG) recordings in 30 adult patients with non-Hodgkin lymphoma (NHL) receiving high-dose CY as part of high-dose chemotherapy (HDT) regimen. All patients were treated with anthracyclines earlier. Heart-rate-corrected QT interval and QT dispersion (QTc and QTc dispersion) were measured from ECG. QRS duration and late potentials (LPs) were analysed from SAECG. Both ECG and SAECG were recorded 1 day (d) prior to HDT (d-7) at baseline, and 1 day (d-2), 7 days (d+7), 12 days (+12) and 3 months (m+3) after HDT. Stem cells were infused on day 0 (d0). Cardiac systolic and diastolic function were assessed on (d-7), (d+12) and (m+3) by radionuclide ventriculography. At baseline, four patients presented with LPs. Cardiac systolic function decreased significantly (53 +/- 2; 49 +/- 2%, P = 0.009 versus baseline), whilst no patient developed acute heart failure. QRS duration prolonged and RMS(40) reduced significantly versus baseline (104 +/- 3; 107 +/- 3 ms, P = 0.003; 41 +/- 4; 38 +/- 3 microV, P = 0.03), and six patients (21%) presented with LPs after CY treatment. Both QTc interval and QTc dispersion increased versus baseline (402 +/- 5; 423 +/- 5 ms, P<0.001; 32 +/- 2; 44 +/- 3 ms, P = 0.012), and six patients (20%) developed abnormal QT dispersion. In conclusion, high-dose CY causes subclinical and transient electrical instability reflected by occurrence of LPs as well as increased QTc interval and QT dispersion. Thus, longer follow-up is required to confirm the meaning of these adverse effects on cardiac function and quality of life.

Fatty fish intake decreases lipids related to inflammation and insulin signaling--a lipidomics approach.

BACKGROUND: The evidence of the multiple beneficial health effects of fish consumption is strong, but physiological mechanisms behind these effects are not completely known. Little information is available on the effects of consumption of different type of fish. The aim of this study was to investigate how fatty fish or lean fish in a diet affect serum lipidomic profiles in subjects with coronary heart disease. METHODOLOGY AND PRINCIPAL FINDINGS: A pilot study was designed which included altogether 33 subjects with myocardial infarction or unstable ischemic attack in an 8-week parallel controlled intervention. The subjects were randomized to either fatty fish (n = 11), lean fish (n = 12) or control (n = 10) groups. Subjects in the fish groups had 4 fish meals per week and subjects in the control group consumed lean beef, pork and chicken. A fish meal was allowed once a week maximum. Lipidomics analyses were performed using ultra performance liquid chromatography coupled to electrospray ionization mass spectrometry and gas chromatography. Multiple bioactive lipid species, including ceramides, lysophosphatidylcholines and diacylglycerols, decreased significantly in the fatty fish group, whereas in the lean fish group cholesterol esters and specific long-chain triacylglycerols increased significantly (False Discovery Rate q-value <0.05). CONCLUSIONS/SIGNIFICANCE: The 8-week consumption of fatty fish decreased lipids which are potential mediators of lipid-induced insulin resistance and inflammation, and may be related to the protective effects of fatty fish on the progression of atherosclerotic vascular diseases or insulin resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT00720655.

NT-proANP and BNP in renovascular and in severe and mild essential hypertension.

BACKGROUND/AIMS: The plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) become increased in hypertension. However, it is unknown what is the effect of the etiology and the severity of hypertension on the plasma concentrations of ANP and BNP. METHODS: We examined plasma levels of ANP (measured as N-terminal fragment of proatrial natriuretic peptide; NT-proANP) and BNP in patients having sustained hypertension of different etiology and severity: in patients with renovascular hypertension (RVHT, n = 12), severe essential hypertension (SEHT, n = 37), and mild essential hypertension (MEHT, n = 29). In addition, we studied the diagnostic value of NT-proANP and BNP to discriminate patients with RVHT from patients with essential hypertension. RESULTS: The plasma concentrations of NT-proANP and BNP were higher in the RVHT group (593 +/- 80 and 25.0 +/- 9.3 pmol/l, respectively) than in the SEHT group (320 +/- 33 and 4.7 + 0.6 pmol/l, respectively; p < 0.001 for both), in spite of the similar blood pressure level, and also higher than in the MEHT group (356 +/- 30 and 7.0 +/- 1.0 pmol/l; p = 0.004 and p = 0.006, respectively). There was no difference in natriuretic peptide levels between the SEHT and MEHT groups. Plasma NT-proANP and BNP correlated positively with aging and serum creatinine concentration and inversely with left ventricular diastolic filling. In addition, NT-proANP correlated positively with systolic blood pressure and BNP with left ventricular mass index. The areas under receiver operating characteristic curves for plasma NT-proANP and BNP to discriminate RVHT patients from patients with essential hypertension were 0.793 and 0.782, respectively. The best cutoff value was 530 pmol/l for NT-proANP, giving a sensitivity of 67% with a specificity of 86%. The cutoff value of 9.8 pmol/l for BNP resulted in a sensitivity of 58% and a specificity of 90%. CONCLUSIONS: Patients with RVHT have higher plasma levels of NT-proANP and BNP than patients with essential hypertension. In addition to the etiology of hypertension, also left ventricular characteristics are important determinants of NT-proANP and BNP concentrations in hypertension. Due to the low sensitivity, NT-proANP and BNP are not suitable as screening tools for RVHT.

Baroreflex sensitivity in essential and secondary hypertension.

Baroreceptor reflex regulation has been shown to reset towards a higher blood pressure level and to operate with reduced sensitivity in hypertension. Whether this is secondary to elevated blood pressure or whether it plays a role in the development of hypertension is not known. In addition, only limited data exist on baroreflex sensitivity (BRS) in patients with long-lasting medically treated essential hypertension and in patients who have blood pressure elevation with similar severity, but of different etiology. The purpose of this study was to examine BRS in patients with different severity and forms of chronic, medically treated hypertension. Patients with renovascular hypertension (RVHT, n = 14), severe essential hypertension (SEHT, n = 36) and mild essential hypertension (MEHT, n = 29) as well as healthy age- and sex-matched control subjects were studied. BRS was measured with the phenylephrine method.BRS in the RVHT (3.7 +/- 0.6 ms/mmHg) and SEHT (7.6 +/- 0.8 ms/mmHg) groups did not differ from each other after age, gender and left ventricular mass index were taken into consideration. On the contrary, BRS in the RVHT (p = 0.008) and SEHT (p = 0.016) groups were lower than in the MEHT (8.5 +/- 1.2 ms/mmHg) group. BRS was also significantly reduced in the RVHT (P = 0.004) and SEHT groups (P = 0.006) when compared to the healthy age- and sex-matched controls. BRS in the MEHT group did not differ from the control subjects. In conclusion, BRS was equally impaired in patients with renovascular and severe essential hypertension, which was similar in severity but different in etiology. BRS in patients with long-lasting medically treated mild essential hypertension did not differ from the healthy subjects. Our study suggests that baroreflex dysfunction in hypertensive patients is related to the clinical severity of hypertension, rather than its etiology.

Short-term blood pressure variability in renovascular hypertension and in severe and mild essential hypertension.

This study was designed to examine short-term blood pressure variability (BPV) in patients with different severity and forms of chronic medically treated hypertension. Power spectral analysis of BPV was performed from continuous finger blood pressure (Finapres) recordings. Ten patients with renovascular hypertension (RVHT), 34 with severe essential hypertension (SEHT) and 29 with mild essential hypertension (MEHT) as well as healthy age- and sex-matched control subjects were studied. The RVHT group was characterized by reduced low frequency (LF) power of both systolic and diastolic BPV (P =0.004 and P =0.003 respectively) when compared with the control group. There was also a tendency to lower total power of diastolic BPV (P =0.094). On the contrary, the SEHT group had increased total power of diastolic BPV (P =0.044). However, in the SEHT group, we found no differences in the LF and high frequency power of systolic and diastolic BPV when compared with controls. The MEHT group presented with lower LF power of systolic and diastolic BPV (P =0.028 and P =0.003 respectively) and, in addition, high frequency power of diastolic BPV was lower than in the control group (P =0.020). When the hypertensive groups were compared with each other, total power and LF power of diastolic BPV (P =0.043 and P =0.039 respectively) were lower in the RVHT group than in the SEHT group. In addition, total power of diastolic BPV was lower (P =0.030) in the MEHT group than in the SEHT group. No differences were observed in BPV between the RVHT and MEHT groups. The results show that BPV in hypertensive patients groups behaved differently. This suggests that both the aetiology and severity of hypertension have a significant influence on short-term BPV measured in laboratory conditions and that different control mechanisms are operating in these clinically distinctly different hypertension groups.

Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study.

Vascular endothelial growth factor (VEGF) gene therapy may be useful for the treatment of lower-limb ischemia. The objectives of this study were to evaluate safety and angiographic and hemodynamic responses of local catheter-mediated VEGF gene therapy in ischemic lower-limb arteries after percutaneous transluminal angioplasty (PTA). For this study, we recruited patients with chronic lower-limb ischemia and atherosclerotic infrainguinal occlusion or stenosis suitable for PTA. In the study, 18 patients received 2x10(10) plaque-forming units (pfu) VEGF-adenovirus (VEGF-Ad), 17 patients received VEGF-plasmid/liposome (VEGF-P/L; 2000 microg of VEGF plasmid, 2000 microl of DOTMA:DOPE), and 19 control patients received Ringer's lactate at the angioplasty site. Digital subtraction angiography (DSA) was used to evaluate vascularity before, immediately after, and 3 months after the PTA. Clinical follow-up data, basic laboratory tests, and ankle-brachial index (ABI) were evaluated. Primary endpoint was DSA analysis of vascularity, and secondary endpoints were restenosis rate, Rutherford class, and ABI after 3 months follow-up. No major gene transfer-related side effects or differences in laboratory tests were detected between the study groups. However, anti-adenovirus antibodies increased in 61% of the patients treated with VEGF-Ad. For the primary endpoint, follow-up DSA revealed increased vascularity in the VEGF-treated groups distally to the gene transfer site (VEGF-Ad P=0.03, VEGFP/L P=0.02) and in the VEGF-Ad group in the region of the clinically most severe ischemia (P=0.01). As for the secondary endpoints, mean Rutherford class and ABI showed statistically significant improvements in the VEGF-Ad and VEGF-P/L groups, but similar improvements were also seen in the control patients. We conclude that catheter-mediated VEGF gene therapy is safe and well tolerated. Angiography demonstrated that VEGF gene transfer increased vascularity after PTA in both VEGF-Ad- and VEGF-P/L-treated groups.