Gregory Chlouverakis

Long-Term Clinical Outcome After Fractional Flow Reserve–Guided Treatment in Patients With Angiographically Equivocal Left Main Coronary Artery Stenosis

Background— Significant left main coronary artery stenosis is an accepted indication for surgical revascularization. The potential of angiography to evaluate the hemodynamic severity of a stenosis is limited. The aims of the present study were to assess the long-term clinical outcome of patients with an angiographically equivocal left main coronary artery stenosis in whom the revascularization strategy was based on fractional flow reserve (FFR) and to determine the relationship between quantitative coronary angiography and FFR. Methods and Results— In 213 patients with an angiographically equivocal left main coronary artery stenosis, FFR measurements and quantitative coronary angiography were performed. When FFR was ≥0.80, patients were treated medically or another stenosis was treated by coronary angioplasty (nonsurgical group; n=138). When FFR was <0.80, coronary artery bypass grafting was performed (surgical group; n=75). The 5-year survival estimates were 89.8% in the nonsurgical group and 85.4% in the surgical group (P=0.48). The 5-year event-free survival estimates were 74.2% and 82.8% in the nonsurgical and surgical groups, respectively (P=0.50). Percent diameter stenosis at quantitative coronary angiography correlated significantly with FFR (r=−0.38, P<0.001), but a very large scatter was observed. In 23% of patients with a diameter stenosis <50%, the left main coronary artery stenosis was hemodynamically significant by FFR. Conclusions— In patients with equivocal stenosis of the left main coronary artery, angiography alone does not allow appropriate individual decision making about the need for revascularization and often underestimates the functional significance of the stenosis. The favorable outcome of an FFR-guided strategy suggests that FFR should be assessed in such patients before a decision is made “blindly” about the need for revascularization.

Efficacy of amiodarone for the termination of persistent atrial fibrillation

The efficacy and safety of amiodarone in the conversion of persistent atrial fibrillation (AF) were investigated in a prospective, randomized, controlled study. Of 67 consecutive patients (32 men, mean age 64+/-9 years) with AF lasting >48 hours, 33 received amiodarone and 34 received placebo. Baseline clinical characteristics were similar in the 2 groups. Patients randomized to amiodarone received 300 mg intravenously for 1 hour and then 20 mg/kg for 24 hours. They were also given 600 mg/day orally, divided into 3 doses, for 1 week and thereafter 400 mg/day for 3 weeks. Patients randomized to placebo received an identical amount of saline IV over 24 hours and then oral placebo for 1 month. Conversion to sinus rhythm was achieved in 16 of the 33 patients (48.5%) who received amiodarone and in none of the 34 patients in the placebo group (p <0.001). None of the patients converted to sinus rhythm within the first 3 days. Those who converted had smaller atria than those who did not (diameter 41.9+/-7.2 vs 50.4+/-5.7 mm, p <0.001). Sex, age, baseline heart rate, left ventricular ejection fraction, and the duration of AF did not differ significantly between patients who converted and those who did not. No side effects requiring discontinuation of treatment were observed in either group. Amiodarone, administered both intravenously and orally, appears to be safe and effective in the termination of persistent AF. Left atrial diameter is the sole independent predictor of conversion.

Changes in atrial electrical properties following cardioversion of chronic atrial fibrillation: relation with recurrence

OBJECTIVE To study the reversibility of atrial electrical remodeling and its relation with recurrence in post-conversion chronic atrial fibrillation (CAF) patients. METHODS In 28 drug-free CAF patients (mean AF duration 41+/-39 months) electrically converted to sinus rhythm effective refractory period (ERP) at 500 ms, monophasic action potential at 90% of repolarization (MAPd90) at five cycle lengths (CL, 350, 400, 450, 500, 600 ms), and P wave duration were measured three times: within the interval 5-20 min post-conversion, 24 h and 1 month later. Fifteen subjects with no history of AF and normal atrial structure served as a control group. Patients were followed up for recurrence for 1 month; 12 relapsed. RESULTS ERP changed from 205+/-20 to 243+/-31 to 241+/-24 ms (P<0. 001), attaining a level comparable to that of the controls (238+/-21 ms) within 24 h. MAPd90 significantly (P<0.001) increased (from 175+/-11 to 190+/-19 to 191+/-10 ms at CL 350 ms and 201+/-12 to 234+/-20 and 233+/-23 ms at CL 600 ms) also reaching control levels within 24 h. MAPd90 exhibited an abnormal adaptation to rate only in the first evaluation. P wave duration was prolonged (137+/-33 ms) and exhibited a slower course of shortening (130+/-32 to 123+/-27 ms, P<0.001), reaching control levels within 1 month. Patients with higher values of MAPd90 at CL 350 in the immediate post-conversion period were more likely to relapse (P<0.005). CONCLUSIONS ERP and repolarization shortening as a result of CAF are reversed within 24 h after conversion, while P wave duration reduces more slowly. Post-conversion MAPd90 values contain prognostic information for recurrence.

Amiodarone versus propafenone for conversion of chronic atrial fibrillation: results of a randomized, controlled study.

OBJECTIVES The purpose of this study was to investigate the efficacy and safety of amiodarone and propafenone in the conversion of chronic atrial fibrillation in a prospective, randomized, placebo-controlled study. BACKGROUND The effectiveness of amiodarone and propafenone in the treatment of patients with chronic atrial fibrillation has not been adequately studied. METHODS One hundred one patients (48 men, mean age 64 +/- 9 years) with atrial fibrillation lasting >3 weeks participated in the study. Thirty-four patients received amiodarone (300 mg intravenously over 1 h, followed by 20 mg/kg over the next 24 h plus 600 mg orally, in three doses, for 1 week, then 400 mg/day orally, for three weeks), 32 received propafenone (2 mg/kg intravenously over 15 min, followed by 10 mg/kg over 24 h and then 450 mg/day orally, for one month) and the remaining 35 served as control subjects. All patients received digoxin and anticoagulant treatment as indicated (International Normalized Ratio 2 to 3). RESULTS Conversion to sinus rhythm was achieved in 16 (47.05%) patients who received amiodarone, in 13 (40.62%) who received propafenone and in none of the control subjects (p < 0.001 for both groups vs. control subjects). Those who converted had smaller atria than those who did not and atrial fibrillation of shorter duration in both the amiodarone and propafenone groups. Treatment was discontinued in one patient of the propafenone group because of significant QRS widening. CONCLUSIONS Amiodarone and propafenone appear to be safe and equally effective in the termination of chronic atrial fibrillation. Left atrial diameter and arrhythmia duration are independent predictors of conversion.

Extracellular Matrix Alterations in Patients With Paroxysmal and Persistent Atrial Fibrillation Biochemical Assessment of Collagen Type-I Turnover

OBJECTIVES We investigated whether the serum markers of collagen turnover differed in various forms of atrial fibrillation (AF) and in sinus rhythm (SR) in humans. BACKGROUND Structural alterations and fibrosis have been implicated in the generation and perpetuation of AF. METHODS Serum C-terminal propeptide of collagen type-I (CICP), C-terminal telopeptide of collagen type-I (CITP), matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinases-1 were measured as markers of collagen synthesis and degradation in 70 patients with AF and 20 healthy control subjects in SR. RESULTS C-terminal propeptide of collagen type-I and CITP were significantly higher in AF patients than in control subjects (91 +/- 27 ng/ml vs. 67 +/- 11 ng/ml, p < 0.001 and 0.38 +/- 0.20 ng/ml vs. 0.25 +/- 0.08 ng/ml, p < 0.001, respectively). Persistent AF patients had higher levels of CICP (105 +/- 28 ng/ml vs. 80 +/- 21 ng/ml, p < 0.001), but not CITP, compared with those with paroxysmal AF. Patients with persistent AF had lower levels of matrix metalloproteinase-1 but increased levels of tissue inhibitor of matrix metalloproteinases-1 compared with patients with paroxysmal AF (11.90 +/- 4.79 ng/ml vs. 14.98 +/- 6.28 ng/ml, p = 0.03 and 155 +/- 45 ng/ml vs. 130 +/- 38 ng/ml, p < 0.001, respectively). Tissue inhibitor of matrix metalloproteinases-1 levels were significantly lower in control subjects compared with those in both paroxysmal and persistent AF patients (102 +/- 15 ng/ml vs. 130 +/- 38 ng/ml vs. 155 +/- 45 ng/ml, respectively, p < 0.001). CONCLUSIONS Serum markers of collagen type-I turnover differed significantly between patients with AF and SR. Furthermore, these markers also differed significantly between paroxysmal and persistent AF patients, suggesting that the intensity of the extracellular synthesis and degradation of collagen type-I may be related to the burden or type of AF.

Activated Vegfr2/kdr Pathway In Tumour Cells And Tumour Associated Vessels Of Colorectal Cancer

Background  Vascular endothelial cell growth factor (VEGF) acts by phosphorylating specific tyrosine kinase receptors on endothelial cell membrane promoting angiogenesis. The study of the activation status of VEGF receptors in human malignancies has recently become feasible by means of specific monoclonal antibodies recognising the phosphorylated form of these receptors.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia on the basis of the revised diagnostic criteria in affected families with desmosomal mutations

Aims To evaluate arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in affected families with desmosome mutations on the basis of the recently revised Task Force Criteria (TFC). Methods and results One hundred and three consecutive carriers of pathogenic desmosome mutations and 102 mutation-negative relatives belonging to 22 families with dominant and 14 families with recessive ARVC/D were evaluated according to the original and revised TFC. Serial cardiac assessment with 12-lead, signal-averaged, and 24 h ambulatory ECG and two-dimensional echocardiography was performed. Clinical events and outcome were prospectively analysed up to 24 years (median 4 years). With the revised criteria, 16 carriers were newly diagnosed on the basis of ECG abnormalities in 100%, ventricular arrhythmias in 79%, and functional/structural alterations in 31%, increasing diagnostic sensitivity from 57 to 71% (P = 0.001). Task Force Criteria specificity improved from 92 to 99% (P = 0.016). In dominant mutation carriers, penetrance changed significantly (61 vs. 42%, P = 0.001); no changes were observed in recessive homozygous carriers (97 vs. 97%, P = 1.00). Affected carriers according to the revised TFC (n = 73) had 12-lead ECG abnormalities in 96%, ventricular arrhythmias in 91%, and functional/structural alterations fulfilling echocardiographic criteria in 76%. Cumulative and event-free survival did not differ significantly between dominant and recessive affected carriers, being at 78.6 vs. 76 and 51.7 vs. 55.4%, respectively, by the age of 40 years. Conclusion Revised TFC increased diagnostic sensitivity particularly in dominant ARVC/D. Serial family evaluation may rely on electrocardiography which seems to have the best diagnostic utility particularly in early disease that is not detectable by two-dimensional echocardiography.

Serum Markers of Collagen Turnover Predict Future Shocks in Implantable Cardioverter-Defibrillator Recipients With Dilated Cardiomyopathy on Optimal Treatment

OBJECTIVES We investigated prospectively whether serum markers of collagen turnover could be used as predictors for the occurrence of malignant ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy (NIDC) who had received an implantable cardioverter-defibrillator (ICD) for primary prevention. BACKGROUND Extracellular matrix alterations in NIDC might provide electrical heterogeneity, thus potentially contributing to the occurrence of ventricular arrhythmia and subsequent sudden cardiac death (SCD). METHODS Serum C-terminal propeptide of collagen type-I, C-terminal telopeptide of collagen type-I, matrix metalloproteinase (MMP)-1, and tissue inhibitor of MMP-1 were measured as markers of collagen synthesis and degradation in 70 patients with mild to moderate symptomatic heart failure due to NIDC with left ventricular ejection fraction <35%, who received an ICD for primary prevention of SCD. Patients were evaluated for any appropriate ICD delivered therapy, whether shock or antitachycardia pacing, during a 1-year follow-up period. RESULTS Appropriate device therapies were delivered in 14 of the 70 patients during the follow-up period, with antitachycardia pacing in 2, antitachycardia pacing with shocks in 4, and shocks in 8. Pre-implantation serum concentrations of C-terminal telopeptide of collagen type-I levels were significantly higher in patients who had appropriate ICD-delivered therapy than in those who did not have any therapy (0.46 +/- 0.19 ng/ml vs. 0.19 +/- 0.07 ng/ml, p < 0.001, respectively). The same was true for baseline MMP-1 and tissue inhibitor of MMP-1 (27.7 +/- 1.6 ng/ml vs. 24.1 +/- 2.5 ng/ml, p < 0.001, and 89 +/- 14 ng/ml vs. 58 +/- 18 ng/ml, p = 0.008, respectively). CONCLUSIONS If the maximum benefit is to be achieved from ICD therapy in NIDC patients for the primary prevention of SCD, a more precise risk stratification is required. As extracellular matrix alterations affect the arrhythmogenic substrate in NIDC, we observed that serum markers of collagen turnover could predict arrhythmic events in ICD recipients.

Reproducibility of tilt table testing in patients with vasovagal syncope and its relation to variations in autonomic nervous system activity.

To assess the variability of head‐ up tilt table testing, 35 patients with vasovagal syncope, shown by a positive tilt table test, underwent a second test 1 week later. Also, on the day before each test, spectral and time‐domain indexes of heart rate variability were derived from Holter recordings to examine the stability of autonomous nervous system activity in these patients. Fifteen healthy volunteers served as a control group and also underwent two tilt table tests with prior Holter monitoring. Twenty‐one (60%) of the 35 patients had a second positive test. None of the patients in the control group experienced syncope during either of the tests. The heart rate variability measures in the control group varied slightly from 1 day to the other, in contrast to the syncopal patients, where only low frequency spectral power and the mean of all 5‐minute standard deviations of RR internals showed comparable behavior. The indexes which reflect parasympathetic activity exhibited significant fluctuations in the syncopal patients. These fluctuations were due entirely to the patients who did not reproduce the outcome of the tilt table test, where high parasympa‐thetic tone was associated with the positive test and normal parasympathetic tone with the negative test. In contrast, the patients with two positive tests had high parasympathetic tone during both test periods, with low individual variability. In conclusion, patients with vasovagal syncope show variations in vagal autonomic tone and appear to be more prone to syncope when their parasympathetic tone is elevated.

The influence of premedication on heart rate variability

Analysis of heart rate variability has been used to study the effects of midazolam, morphine and clonidine on the autonomic nervous system, when administered to patients for premedication. Ninety‐five patients were studied 60 min before and 60 min after premedication. Normal saline (n = 25), midazolam 0.08 mgkg−1 (n = 24), morphine 0.15 mgkg−1 (n = 23), or clonidine 2 μgkg−1 (n = 23) were administered intramuscularly by random allocation. A Holter device was connected to the patient during the study period. Using power spectral analysis the low‐frequency and high‐frequency components were calculated from the Holter recordings. These are markers for sympathetic and parasympathetic activity respectively; the low‐ to high‐frequency ratio was also calculated, a ratio of >1 signifying sympathetic dominance. A significant reduction was noticed in both low‐frequency and high‐frequency power in the three premedicated groups, whereas no changes were observed in the normal saline group. In the case of midazolam, both the low and high frequencies were decreased but the low‐ to high‐frequency ratio did not change significantly. Morphine and clonidine depressed the low‐frequency component more than the high‐frequency component and the low‐ to high‐frequency ratio was decreased, suggesting parasympathetic dominance. We conclude that heart rate variability may be a useful tool for investigating the effect of drugs on the autonomic nervous system.