Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study.

In phase I KAT301 trial, intramyocardial adenovirus-mediated vascular endothelial growth factor -DΔNΔC (AdVEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved symptoms in refractory angina patients at 1-year follow-up without major safety concerns. We investigated the long-term safety and efficacy of AdVEGF-D GT. 30 patients (24 in VEGF-D group and 6 blinded, randomized controls) were followed for 8.2 years (range 6.3-10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse event (MACE) and other predefined safety endpoints. MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.97; 95% confidence interval 0.36-2.63; P = 0.95). Mortality and new-onset comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P = 0.006) but not in control group (2.2 vs. 2.6; P = 0.414). Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up.

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.

Myocardial ischemia and previous infarction contribute to left ventricular dyssynchrony in patients with coronary artery disease.

AIMS: The aim of this study was to characterize determinants of left ventricular mechanical dyssynchrony (LVMD) in patients with coronary artery disease (CAD). METHODS: Medical records and results of myocardial perfusion SPECT/CT studies were evaluated in 326 patients with previously diagnosed CAD. LVMD was assessed with the phase analysis of ECG-gated myocardial SPECT. Dyssynchrony was described with phase histogram bandwidth (PHBW), standard deviation (PHSD) or entropy (PHE) values above limit of the highest normal. RESULTS: Prevalence of LVMD was 29% in CAD patients. Size of the infarction scar and ischemia extent correlated significantly with PHBW, PHSD and PHE (P < 0.001 for all). Independent predictors of LVMD were myocardial infarction scar (P = 0.004), ischemia extent (P = 0.003), and QRS duration (P = 0.003). Previous percutaneous coronary intervention and coronary artery bypass grafting did not independently predict dyssynchrony. CONCLUSIONS: Almost one-third of CAD patients had significant LVMD. Dyssynchrony was associated with earlier myocardial infarction and presence of myocardial ischemia. Previous percutaneous coronary intervention and coronary artery bypass grafting did not independently predict dyssynchrony.

Relationships between electrical and mechanical dyssynchrony in patients with left bundle branch block and healthy controls.

BACKGROUND: Abnormal electrical activation may cause dyssynchronous left ventricular (LV) contraction. In this study, we characterized and analyzed electrical and mechanical dyssynchrony in patient with left bundle branch block (LBBB) and healthy controls. METHODS: Myocardial perfusion imaging (MPI) data from 994 patients were analyzed. Forty-three patient fulfilled criteria for LBBB and 24 for controls. Electrical activation was characterized with vector electrocardiography (VECG) and LV function including mechanical dyssynchrony with ECG-gated MPI phase analysis. RESULTS: QRS duration (QRSd; r = 0.69, P < .001) and a few other VECG parameters correlated significantly with phase bandwidth (phaseBW) representing mechanical dyssynchrony. End-diastolic volume (EDV; r = 0.59, P < .001), ejection fraction and end-systolic volume correlated also with phaseBW. QRSd (ß = 0.47, P < .001) and EDV (ß = 0.36, P = .001) were independently associated with phaseBW explaining 55% of its variation. Sixty percent of patients with LBBB had significant mechanical dyssynchrony. Those patients had wider QRSd (159 vs 147 ms, P = .013) and larger EDV (144 vs 94 mL, P = .008) than those with synchronous LV contraction. Cut-off values for mechanical dyssynchrony seen in patients with LBBB were QRSd ≥ 165 ms and EDV ≥ 109 mL. CONCLUSIONS: Despite obvious conduction abnormality, LBBB is not always accompanied by mechanical dyssynchrony. QRSd and EDV explained 55% of variation seen in phaseBW. These two parameters were statistically different between LBBB cases with and without mechanical dyssynchrony.

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.

Heart rate variability associates with asymptomatic coronary atherosclerosis.

PURPOSE: Heart rate variability (HRV) becomes impaired in symptomatic coronary artery disease (CAD), particularly, after myocardial infarction. The mechanism how CAD results in impairment of cardiac autonomic regulation is not known. Whether it results rather from coronary atherosclerosis itself than myocardial ischemia and myocardial injury has remained elusive. METHODS: Quantitative coronary angiography was performed in 30 subjects without history of myocardial ischemia, but with high familial risk for CAD. HRV was measured from 24-h ambulatory ECG recordings in time and frequency domain and also non-linear HRV variables SD1 and SD2 in Poincare plot were calculated. Myocardial ischemia was excluded by Tc-99m sestamibi scintigraphy at rest and during exercise. RESULTS: Coronary angiography revealed mean diameter stenosis of 32 ± 19 % in left anterior descending coronary artery, 26 ± 16 % in left circumflex coronary artery and 25 ± 20 % in right coronary artery. An inverse correlation was found between pNN50 and global severity of coronary artery diameter stenosis (r = -0.415, p < 0.05). Correspondingly, power of HF spectral component correlated negatively with global extent of coronary atherosclerosis (r = -0.366, p < 0.05). In Poincare plot, SD1/SD2 ratio correlated with global extent (r = -0.394, p < 0.05) and global burden (r = -0.388, p < 0.05) of coronary arteries. CONCLUSIONS: The severity and extent of coronary atherosclerosis were related to a shift of cardiac autonomic regulation towards sympathetic predominance in asymptomatic subjects without evidence of myocardial ischemia.

Myocardial (123) I-metaiodobenzylguanidine washout and heart rate variability in asymptomatic subjects.

BACKGROUND: Myocardial (123) I-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. METHODS: We evaluated the relationship between myocardial MIBG washout and HRV in 30 asymptomatic subjects with familial risk of coronary artery disease (CAD). Early and delayed myocardial MIBG uptakes as well as MIBG washout between these two scans were assessed. Myocardial perfusion at rest and during bicycle exercise was evaluated with (99m) Tc-sestamibi (MIBI). HRV was measured from 24-hour ambulatory ECG recordings. RESULTS: Myocardial MIBG washout averaged 40 ± 8%. The mean heart rate at rest was 76 ± 14 beats/min. Standard deviation of all normal RR intervals (SDNN) was 94 ± 22 ms and very low frequency (VLF) was 1625 ± 958 ms(2) on average. Myocardial MIBG washout correlated inversely with SDNN (r =-0.390; P < 0.05) and with VLF (r =-0.459; P < 0.01) component of HRV but not with heart rate at rest (r = 0.207, P = ns). All subjects had normal myocardial perfusion at rest and during exercise. CONCLUSIONS: Increased cardiac presynaptic sympathetic nervous activity was related to reduced HRV in subjects with the risk of CAD but without evidence of myocardial ischemia or previous myocardial infarction. In addition, we found that VLF component of HRV includes information about sympathetic neural modulation of the heart rate.

Cardiac remodelling in association with left ventricular dyssynchrony and systolic dysfunction in patients with coronary artery disease.

BACKGROUND: In patients with coronary artery disease (CAD), ischaemic cardiomyopathy may result in progressive cardiac remodelling and left ventricular (LV) dysfunction. Myocardial perfusion imaging (MPI) can be used to quantify LV size and shape, mechanical dyssynchrony (LVMD) and ejection fraction (EF) as well as myocardial ischaemia and injury extents. We investigated the prevalence of LV remodelling (LVR) in patients with CAD and the relationship between LVR, LVMD and EF. METHODS: Three hundred twenty-six patients with CAD were evaluated. The EF and end-diastolic volume (EDV) were measured using MPI. LVMD was assessed using phase analysis. LVR was characterised according to LV dilatation or increased shape indices (systolic shape index [SIES] and diastolic shape index [SIED]). RESULTS: LVR were observed in 41% of CAD patients. EDV, SIES and SIED were larger in patients with LVMD or low EF. After adjustment for age, sex and infarct and ischaemia extents, phase histogram bandwidth correlated with EDV (r = 0.218) and SIES (r = 0.266) and EF correlated with EDV (r = -0.535), SIES (r = -0.554) and SIED (r = -0.217, p < 0.001 for all). CONCLUSIONS: LVR is frequently seen in patients with CAD and may be detected even before the development of symptomatic heart failure. A large LV volume and a more spherical-shaped LV were associated with LVMD and low EF, highlighting the close relationships between remodelling and systolic dyssynchrony and dysfunction. MPI is useful for assessing LVR by providing information about LV size and shape, which changes from an ellipsoid towards a spherical form in the development of ischaemic cardiomyopathy.

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. METHODS: We analyzed mean normal-to-normal R-R intervals, short-term scaling exponent of detrended fluctuation analysis (DFA alpha(1)), approximate entropy and entropy of symbolic dynamics (SymDyn En) from 10-minute ECG recordings during rest, paced breathing, and passive tilt performed 1 day before surgery in 67 elective coronary artery bypass grafting patients. RESULTS: Nineteen patients developed postoperative atrial fibrillation. The preoperative DFA alpha(1) was constantly lower in patients developing postoperative atrial fibrillation than in patients remaining in sinus rhythm (P = 0.016); during spontaneous breathing, the DFA alpha(1) was 0.93 +/- 0.33 in patients with atrial fibrillation and 1.13 +/- 0.24 in patients with sinus rhythm. The entropy of symbolic dynamics was higher during the spontaneous breathing in patients with atrial fibrillation than in patients with sinus rhythm (4.72 +/- 0.51 vs 4.36 +/- 0.51, P = 0.012). Higher short-term scaling exponent of detrended fluctuation analysis during the spontaneous breathing period reduced the risk of postoperative atrial fibrillation (OR 0.31 for an interquartile increase in DFA alpha(1), 95% CI 0.13-0.78), while higher entropy of symbolic dynamics increased it (OR 3.16 for an interquartile increase in SymDyn En, 95% CI 1.23-8.10), independently of age and clinical risk factors. CONCLUSION: The preoperatively altered nonlinear R-R interval dynamics were independent predictors of postoperative atrial fibrillation and might become a useful tool for the risk assessment of atrial fibrillation.

Reference values for left ventricular systolic synchrony according to phase analysis of ECG-gated myocardial perfusion SPECT.

BACKGROUND: The aim of this study was to define reference values for left ventricular systolic synchrony and for the volume parameters of the left ventricle using myocardial perfusion SPECT-derived phase analysis method. METHODS: We evaluated data of 433 patients who underwent myocardial perfusion SPECT/CT during January 2012-February 2013 in Kuopio University Hospital. The final study population consisted of 52 patients (aged 42-84 years) who met the criteria: (1) no previously diagnosed cardiac disease, (2) normal ECG at rest, (3) no advanced coronary artery disease in CT and 4) normal myocardial perfusion in stress/rest myocardial perfusion SPECT/CT. The severity of mechanical dyssynchrony was assessed by phase analysis of gated myocardial SPECT at stress stage after pharmacological exercise and at rest using Quantitative Gated SPECT (QGS) software. Volume parameters of the left ventricle were also assessed. RESULTS: The phase histogram bandwidth at rest was 28.0 [63.7] degrees (median [95th percentile]). The standard deviation of phase histogram at rest was 7.8 [26.5] degrees. Entropy at the rest study was 54.0 [63.7] %. All left ventricular dyssynchrony parameters were statistically significantly higher at stress compared to rest. There were no statistically significant differences in dyssynchrony values between men and women. In volume parameters, reference values in male were expectedly higher than in female. Cardiac output did not differ significantly between genders. CONCLUSION: In subjects without signs of cardiac diseases, the left ventricular systolic function is well synchronized. Phase analysis measurement does not depend on gender, age, BMI or blood pressure, but the values of dyssynchrony parameters increase during pharmacological stress.

Intramyocardial Gene Therapy Directed to Hibernating Heart Muscle Using a Combination of Electromechanical Mapping and Positron Emission Tomography.

Cardiac gene transfer for the treatment of ischemic diseases has suffered from low gene transfer efficiency and inability to target treatment genes to the ischemic myocardium. A combined method has been developed based on electromechanical mapping and radiowater PET imaging to target gene therapy to viable but ischemic and hibernating areas of the myocardium. Electromechanical NOGA mapping produces three-dimensional images of myocardium with both an electric activity map and a myocardial contractility map. These have been converted to 17-segment 2D bull's-eye maps, which were superimposed onto PET radiowater perfusion imaging maps of the myocardium. This technique was applied in a Phase I/IIa clinical trial to target gene therapy for refractory angina patients. It was found that by combining electromechanical map with PET imaging, targeting of gene therapy to hibernating ischemic myocardium can be significantly improved. Here, the methods for the identification of viable, ischemic, and hibernating myocardium for gene transfer are described, and examples of treated refractory angina patients who have benefited from the improved gene transfer method to the ischemic myocardium are presented.

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 (2x10(11) and 2x10(12) viral particles) or naked plasmids (1 mg) encoding LacZ control, VEGF-A165, or the mature, soluble form of VEGF-D (VEGF-D(DeltaNDeltaC)) were injected intramyocardially with the NOGA catheter system into domestic pigs. AdVEGF-D(DeltaNDeltaC) 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 alpha-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(DeltaNDeltaC) 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(DeltaNDeltaC) GT using the NOGA system produces efficient transmural angiogenesis and increases myocardial perfusion. AdVEGF-D(DeltaNDeltaC) could be useful for the induction of therapeutic vascular growth in the heart.

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.

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.

Fractal correlation properties of R-R interval dynamics in asymptomatic relatives of patients with dilated cardiomyopathy.

BACKGROUND AND AIM: asymptomatic relatives of patients with familial dilated cardiomyopathy who have left ventricular enlargement [LVE] are at risk for progression to dilated cardiomyopathy. A novel index of the fractal correlation properties of heart rate variability (HRV), the short-term scaling component (proportional, variant(1)) in detrended fluctuation analysis, is a promising prognostic tool in left ventricular dysfunction. The aim of this study was to compare values of proportional, variant(1) and conventional HRV indices in LVE relatives with dilated cardiomyopathy patients and normal controls. METHODS: time-domain and spectral HRV measures, and the short-term scaling component ( proportional, variant(1)) were assessed from 24-h Holter recordings from 22 LVE relatives (left ventricular end-diastolic dimension >112% predicted, normal fractional shortening), 24 dilated cardiomyopathy patients and 14 controls. RESULTS: the time domain index SDNN was lower in dilated cardiomyopathy patients [101.8(+/-44.0)] than in LVE relatives [161.7(+/-53.9)] or controls [152.9(+/-51.4)], P=0.01. Similarly, triangular index and spectral measures were reduced in dilated cardiomyopathy patients but not in LVE relatives or controls. In contrast, the short term scaling component ( proportional, variant(1)) in detrended fluctuation analysis was reduced in both dilated cardiomyopathy patients [1.06(+/-0.33)] and in LVE relatives [1.15 (+/-0.20)], compared with controls [1.32(+/-0.16)], P=0.01. Among DCM patients the short-term scaling component ( proportional, variant(1)) was significantly associated with echocardiographic deterioration during follow-up (3.7+/-2.1 year) (P=0.004). CONCLUSION: the short-term scaling component ( proportional, variant(1)) is reduced in asymptomatic relatives of dilated cardiomyopathy patients who have LVE.

Baroreflex sensitivity in asymptomatic coronary atherosclerosis.

BACKGROUND: 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. METHODS: The relationship between BRS and coronary atherosclerosis was evaluated in 31 subjects with high familial risk for CAD but without evidence of angina pectoris or myocardial ischaemia. Single photon emission tomography was performed with (99m) Tc-sestamibi to rule out myocardial perfusion defects at rest and during exercise. BRS was assessed by phenylephrine technique. Coronary atherosclerosis was analysed by quantitative coronary angiography (QCA). Percentage of diameter stenosis (PDS) was calculated separately for LAD, LCX, RCA coronary arteries as well as for proximal (PROX), middle (MID) and distal (DIST) coronary artery regions; and for all coronary artery regions (global PDS). RESULTS: Baroreflex sensitivity averaged 7·8 ± 5·4 ms mmHg(-1) . BRS showed inverse correlation to PDS of the proximal coronary artery segments (r = -0·315; P<0·05) and with the most severe single coronary artery stenosis (r = -0·374; P<0·05). Five (16%) subjects had BRS ≤ 3 ms mmHg(-1) . They had more severe PDS of proximal coronary artery segment than subjects with BRS > 3 ms mmHg(-1) (24 ± 7% versus 13 ± 11%, P<0·05, respectively). CONCLUSIONS: Impairment of BRS was found to be associated with the severity of subclinical coronary atherosclerosis in healthy asymptomatic subjects with familial risk of CAD. Asymptomatic subjects with severely blunted BRS may have advanced coronary atherosclerosis.

Microvolt T-wave alternans during exercise and pacing in patients with acute myocardial infarction.

Cardiac Arrhythmias and Risk Stratification after Myocardial infarction (CARISMA) is a prospective multicenter trial designed to document the incidence of cardiac arrhythmias after acute myocardial infarction (AMI), and to assess the predictive accuracy of various arrhythmic risk markers. In this substudy of the CARISMA trial, microvolt T-wave alternans (TWA) was assessed with specific equipment 6 weeks after AMI during bicycle exercise, atrial (A) pacing, and simultaneous ventricular and atrial (V + A) pacing in 80 patients with left ventricular ejection fraction (LVEF) <40%. The agreement between the acute test results was determined by overall proportion of concordance and the kappa statistic. Sustained TWA was observed in 24, 45, and 50% of the patients during the exercise test, A pacing, and V + A pacing, respectively. The number of indeterminate TWA was significantly lower during V + A pacing (n = 7) than exercise test (n = 34). The TWA concordance rate was 71% between exercise and V + A pacing (kappa= 0.53, P = 0.001), 79% between exercise and A pacing (kappa= 0.54, P < 0.001), and 95% between the two pacing modes (kappa= 0.89, P < 0.001). Patients with positive TWA in all tests had lower LVEF (28 +/- 7% vs 35 +/- 9%, P < 0.01) and wider QT dispersion (99 +/- 44 ms vs 67 +/- 38 ms, P < 0.01) than those with inconsistent test result. The low number of indeterminate tests and high concordance between the test results indicate that V + A pacing may provide a valuable means to assess TWA in patients who cannot complete the exercise test.

Right atrial overdrive pacing does not prevent atrial fibrillation after coronary artery bypass surgery.

AIMS: The purpose of this prospective randomized study was to investigate the efficacy of atrial overdrive pacing (AOP) and bradycardia prevention pacing (BPP) in the prophylaxis of atrial fibrillation (AF) after coronary artery bypass surgery (CABG). METHODS: One hundred and twenty-four on-pump CABG patients were randomized into three groups: AOP, BPP, and NP (no pacing). AOP patients were paced via epicardial wires using an atrial preference pacing algorithm, and BPP patients were paced in the AAI mode with a base rate of 60/min. Patients were paced for 48 h starting on the first postoperative day. The endpoint of the study was the first onset of AF lasting longer than 5 min. RESULTS: Preoperative risk factors and surgical data of patients did not differ between the AOP, BPP and NP groups. Pacing was technically successful in 80.5% of patients in the AOP and in 92.7% in the BPP groups. The incidence of AF in the AOP (26.8%), BPP (19.5%) and NP (28.6%) groups did not differ significantly. In the AOP group, AF in three patients was probably induced by inappropriate pacing due to sensing failure. CONCLUSIONS: Atrial overdrive pacing and bradycardia prevention pacing were not effective in the prevention of AF after CABG.

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. beta-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.

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.