Usefulness of noninvasive MSCT coronary angiography as first-line imaging technique in patients with chest pain: initial clinical experience.

PURPOSE: Comparative studies with invasive coronary angiography (ICA) indicated a good sensitivity and specificity in the noninvasive detection of coronary artery disease (CAD) using Multi-slice spiral computed tomography coronary angiography (MS-CTA). The aim was to investigate the usefulness of MS-CTA as first-line imaging technique in patients (pts) with known or suspected CAD and low to intermediate probability of a severe coronary lesion. We report on our initial clinical experience using MS-CTA without compelled ICA. MATERIAL AND METHODS: One hundred thirty six patients with chest pain underwent MS-CTA on an outpatient basis (age 60+/-10, suspicion of CAD: n=95, suspicion of restenosis: n=24, after CABG: n=17). Based on the MS-CTA results, a recommendation concerning further diagnostics and therapy was given to each pt. A telephone interview was performed after 455+/-166 days to evaluate the further clinical course. RESULTS: Per pt, 8.2+/-2.7 coronary segments could be evaluated. Based on the MSCT results, the presence of flow-limiting stenoses was excluded in n=77 (57%) pts (group I). An additional ICA was recommended in n=59 (43%) pts (group II). An ICA had been performed in meantime in 27/136 (20%) pts, and could be avoided in the majority of pts. Nevertheless, 58/136 (42%) pts reported on improved clinical symptoms and 42/136 (31%) pts of improved quality of life. CONCLUSIONS: MS-CTA was found to be useful to evaluate the need and to reduce the total number of ICA in pts with unclear chest pain. It appears to be the first noninvasive modality, which might be used on a clinical routine basis in selected groups of pts.

Long-term experience with subcutaneous ICD leads: a comparison among three different types of subcutaneous leads.

ICDs provide protection against sudden cardiac death in patients with life-threatening arrhythmias. Nevertheless, efficacy of defibrillation remains an important issue to guarantee the future safety of patients who receive an ICD. There is a significant number of patients who need an additional subcutaneous lead to obtain a defibrillation safety margin of at least 10 J between the maximum output of the ICD and the energy needed for ventricular defibrillation. However, few data exists about the long-term performance of different types of subcutaneous leads. Therefore, the aim of this study was to analyze the long-term experience with three different types of subcutaneous leads. The study included 132 patients (109 men, 23 women; mean age 59.8 years [SD +/- 10.7 years]). All of them received a subcutaneous lead in addition to a single chamber or dual chamber ICD between October 1990 and April 2002. Two patients received a second subcutaneous lead after the first lead had been removed so that a total of 134 subcutaneous leads were evaluated. Inclusion criteria for the implantation of an additional subcutaneous lead were (1) unsuccessful ventricular defibrillation at implant without a subcutaneous lead, (2) insufficient safety margin (< 10 J) between the maximum output of the ICD and the energy needed for ventricular defibrillation, or (3) clinical evaluation of a new subcutaneous lead (Medtronic 13014). There were no significant differences between the three study groups with regard to age, sex, underlying cardiac disease, left ventricular ejection fraction, NYHA class assessment and clinical arrhythmia. The results of the DFT testing during follow-up (prehospital discharge test and 1 and 3 years) were compared to the baseline value obtained during the implantation procedure. All lead related complications were analyzed. Eighty-two single element subcutaneous array electrodes (SQ-A1), 31 subcutaneous three-finger electrodes (SQ-A3), and 21 subcutaneous patch electrodes (SQ-P) were implanted during the study period. The median follow-up was 1,499 days (25th percentile: 798 days, 75th percentile: 1,976 days) in the SQ-A1 group, 2,209 days (25th percentile: 1,242 days, 75th percentile: 2,710 days) in the SQ-A3 group, and 1,419 days (25th percentile: 787 days, 75th percentile: 2,838 days) in the SQ-P group. None of the three groups had a significant change of the DFT during follow-up compared to baseline. Major complications occurred in six (7.3%) patients in group SQ-A1 and in two (9.5%) patients in group SQ-P. There were no major complications in group SQ-A3. Kaplan-Meier curves analyzing freedom from subcutaneous lead related complications did not show a significant difference between the three study groups (P = 0.16). SQ-A1, SQ-A3, and SQ-P leads provide stable DFTs during long-term follow-up. Major complications are rare. However, a careful follow-up including chest radiographs at regular intervals is needed to detect potentially fatal complications like lead fractures.

Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial.

AIMS: In patients with persistent atrial fibrillation (AF), the efficacy and safety of two anti-arrhythmic drugs in preventing the recurrence of AF after successful direct current (DC) cardioversion was prospectively assessed in a multi-centre double-blind, placebo-controlled, randomised trial using daily trans-telephonic monitoring. METHODS AND RESULTS: 1182 patients with persistent AF were prospectively enrolled, 848 patients were successfully cardioverted and then randomised to either sotalol (383 patients), quinidine plus verapamil (377 patients) or placebo (88 patients). The primary outcome parameter was AF recurrence or death. All patients received an event recorder (Tele-ECG) and had to record and transmit via telephone at least one ECG per day during follow-up. The mean follow-up period was 266 days. A total of 191,103 Tele-ECGs were recorded and transmitted. The primary outcome parameter (AF recurrence of any kind or death) was observed in 572 patients (67%) in whom at least one episode of AF recurrence was documented during follow-up, in 348 patients (41%) AF recurrence was persistent. The recurrence rates after one year for any AF were 83% for placebo, 67% for sotalol and 65% for quinidine plus verapamil, the latter being statistically superior to placebo but not different from sotalol. The recurrence rates for the secondary outcome parameter persistent AF were 77%, 49% and 38%, respectively. Quinidine plus verapamil was significantly superior to placebo and to sotalol. About 95% of all AF recurrences were initially detected in the daily Tele-ECG, about 70% of all AF recurrences occurred completely asymptomatic. Adverse events on sotalol and quinidine plus verapamil were comparable with the exception that all torsade de pointes tachycardias occurred on sotalol. CONCLUSION: Anti-arrhythmic treatment after DC cardioversion of persistent AF significantly decreases the recurrence rates of persistent AF compared to placebo with superiority of quinidine plus verapamil compared to sotalol. Symptoms were not reliable as clinical surrogates to detect episodes of AF.

Relationship between minor myocardial damage and inflammatory acute-phase reaction in acute coronary syndromes.

BACKGROUND: In severe acute coronary syndromes (ACS) elevation of markers of inflammation and acute phase reaction (APR) like C-reactive protein (CRP) as well as a release of troponin have been reported. Using a high sensitivity troponin T (TnT) test we investigated whether an APR occurs in ACS only in the presence of ischemic myocardial damage. METHODS: In 85 patients with ACS C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, thrombin antithrombin III complexes (TAT) and kallikrein were determined vs. high sensitive TnT (> or =0.02 ng/ml) initially and 2 d later vs. 45 patients with stable angina pectoris and 42 controls. RESULTS: In stable angina pectoris, markers of inflammation and coagulation were slightly elevated (p < 0.05). Initially in ACS elevations of CRP to 1.2 +/- 0.3 mg/dl, SAA to 4.8 +/- 2.6 mg/dl and fibrinogen to 448 +/- 21 mg/dl (all p < 0.01 vs. controls) were found followed by a significant APR (p < 0.01). In the subgroup of TnT positive ACS patients, an APR with increased CRP (4.1 +/- 1.3 mg/dl), SAA (20.4 +/- 8.3 mg/dl), and fibrinogen (641 +/- 45 mg/dl) was detectable (all p < 0.05 vs. TnT negative patients). In contrast, patients without TnT release showed APR markers comparable to patients with stable angina pectoris. CONCLUSION: Our findings demonstrate an association between myocardial injury in ACS and acute phase reaction as evidenced by several molecular markers. A highly sensitive TnT-test identified myocardial injury in about all patients with APR while a standard TnT cut-off (0.1 ng/ml) missed 32% of these patients. Thus, the APR in patients with ACS is strongly associated with at least minor ischemic myocardial damage and prior findings of an APR independent from myocardial injury are probably based on less sensitive troponin tests.

Delayed sodium channel inactivation mimics long QT syndrome 3.

DPI 201-106 delays sodium channel inactivation. Acute administration of DPI 201-106 prolonged the QT interval, provoked spontaneous torsades de pointes in one patient, and facilitated stimulation-induced polymorphic ventricular tachyarrhythmias in two patients. Similar to the observations in animal studies, delaying sodium channel inactivation is a new form of the acquired long QT syndrome, mimicking long QT syndrome type 3.

Effects of the chromanol HMR 1556 on potassium currents in atrial myocytes.

PURPOSE: The chromanol HMR 1556 is a potent blocker of KvLQT1/minK potassium channels expressed in Xenopus oocytes. The compound is therefore a new class III antiarrhythmic drug with a distinct mechanism of action. However, the effect of HMR 1556 on atrial ion channels and the selectivity of block in the human heart has not been investigated. We tested the effects of HMR 1556 on repolarizing potassium currents in human and guinea pig atrial myocytes. METHODS AND RESULTS: Single atrial myocytes were isolated by enzymatic dissociation. Atrial potassium currents (I(Ks), I(Kr), in guinea pig, I(to), I(Kur), I(K1) in humans) were recorded at 36 degrees C in the whole cell mode of the patch clamp technique. HMR 1556 produced a concentration-dependent and reversible block of I(Ks) with a half maximal concentration (EC(50)) of 6.8 nmol/l. 10 micromol/l HMR 1556 almost completely inhibited I(Ks) (97.2+/-3.2%, n=6). Steady-state activation as well as kinetic properties of the current were not altered by HMR 1556. I(Kr) currents were not affected up to concentrations of 10 micromol/l. HMR 1556 did not inhibit other potassium currents in human atrium: I(to), I(Kur) and the classical inward rectifier potassium current I(K1) were not significantly affected up to concentrations that completely blocked I(Ks) (10 micromol/l). CONCLUSIONS: HMR 1556 is a highly-potent blocker of I(Ks) channels without exerting effects on other potassium currents involved in atrial repolarization. Given the potential advantages of I(Ks) vs. I(Kr) blockade, the drug's new mechanism of action warrants further investigation to clarify its role as an antiarrhythmic agent.

Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I(Ca,L) and I(to) in rapid atrial pacing in rabbits.

OBJECTIVES: The purpose of the study was to characterize the ionic and molecular mechanisms in the very early phases of electrical remodeling in a rabbit model of rapid atrial pacing (RAP). BACKGROUND: Long-term atrial fibrillation reduces L-type Ca(2+) (I(Ca,L)) and transient outward K(+) (I(to)) currents by transcriptional downregulation of the underlying ionic channels. However, electrical remodeling starts early after the onset of rapid atrial rates. The time course of ion current and channel modulation in these early phases of remodeling is currently unknown. METHODS: Rapid (600 beats/min) right atrial pacing was performed in rabbits. Animals were divided into five groups with pacing durations between 0 and 96 h. Ionic currents were measured by patch clamp techniques; messenger ribonucleic acid (mRNA) and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot, respectively. RESULTS: L-type calcium current started to be reduced (by 47%) after 12 h of RAP and continued to decline as pacing continued. Current changes were preceded or paralleled by decreased mRNA expression of the Ca(2+) channel beta subunits CaB2a, CaB2b, and CaB3, whereas significant reductions in the alpha(1) subunit mRNA and protein expression began 24 h after pacing onset. Transient outward potassium current densities were not altered within the first 12 h, but after 24 h, currents were reduced by 48%. Longer pacing periods did not further decrease I(to). Current changes were paralleled by reduced Kv4.3 mRNA expression. Kv4.2, Kv1.4, and the auxiliary subunit KChIP2 were not affected. CONCLUSIONS: L-type calcium current and I(to) are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.

Effects of cerivastatin on human arterial smooth muscle cell growth and extracellular matrix expression at varying glucose and low-density lipoprotein levels.

Statins exert pleiotropic effects on several other cellular functions besides lipid-lowering. Previously, it was found that cerivastatin is a very potent inhibitor of human arterial smooth muscle cell (haSMC) growth. However, because increased extracellular matrix (ECM) synthesis also accounts mainly for intimal plaque formation, the effects of cerivastatin on ECM expression was examined in this study. Furthermore, the influence of varying glucose and low-density lipoprotein (LDL) levels on cerivastatin-treated haSMCs was analyzed to mimic the conditions in patients with diabetes or hypercholesterolemia. The haSMCs were treated with 0.001-5.0 microM cerivastatin in the presence of 5.5-18.9 m glucose and 10-1000 microg/ml LDL. After 3 days, the messenger RNA (mRNA) expression of eight ECM proteins was analyzed and, after 7 days, mitotic and mitochondrial activities and thrombospondin (TSP)-1 protein expression were analyzed. TSP-1 and TSP-2 mRNA expression was inhibited highly significantly at cerivastatin doses >or=0.01 microM with maximums of 72% and 35%, respectively, at high glucose levels. The mRNA signals of the third glycoprotein fibronectin were not influenced. Furthermore, collagen-1 mRNA was inhibited highly significantly up to 71% and biglycan mRNA was similarly inhibited up to 45%. The mRNA expression of the matrix-stimulating transforming growth factor (TGF)-beta1 and matrix metalloproteinase (MMP)-2 was not altered significantly, whereas mRNA expression of the tissue inhibitor of metalloproteinase (TIMP)-2 was stimulated clearly up to 150%. Mevalonate, but not LDL replacement, reversed the effects. Immunofluorescence staining showed an unaltered TSP-1 pattern with cerivastatin doses up to 0.1 microM whereas higher doses impaired TSP-1 excretion. The effects of cerivastatin on haSMC growth and mRNA expression of the eight ECM components were not diminished by the increase in LDL and glucose levels. Since accelerated SMC growth and ECM formation contribute mainly to intimal thickening, cerivastatin may be protective against the development of atherosclerotic and restenotic lesions by its direct cellular effects. Increased LDL and glucose levels, as in diabetes, do not mitigate the beneficial effects of cerivastatin on cell growth and ECM formation in vitro.

beta3-Adrenergic regulation of an ion channel in the heart-inhibition of the slow delayed rectifier potassium current I(Ks) in guinea pig ventricular myocytes.

OBJECTIVES: I(Ks), the slow component of the delayed rectifier potassium current, underlies a strong beta-adrenergic regulation in the heart. Catecholamines, like isoproterenol, induce a strong increase in I(Ks). Recent work has pointed to an opposing biological effect of beta(1)- and beta(3)-adrenoceptors in the heart. However the role of these subtypes in the regulation of cardiac ion channel function is unknown. METHODS: We investigated the effects of beta(1)- and beta(3)-adrenoceptor modulation on I(Ks) in guinea-pig ventricular myocytes, using patch-clamp techniques. RESULTS: Superfusion with 100 nmol/l isoproterenol increased the step current amplitude by 81.3+/-8.0%. In contrast, after block of beta(1)- (1 micromol/l atenolol) and beta(2)-receptors (1 micromol/l ICI118,551), isoproterenol induced a reduction of the step current amplitude by 34.3+/-3.5%. The beta(3)-selective agonist BRL37344 significantly reduced the I(Ks) step current at +70 mV in a concentration-dependent manner (IC(50): 5.01 nmol/l). In the presence of bupranolol (beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist), the effect of BRL37344 was markedly attenuated, from 27.3+/-5.6% (100 nmol/l BRL37344 alone) to 4.0+/-1.3% (100 nmol/l BRL37344+1 micromol/l bupranolol). BRL37344 (100 micromol/) did not alter current amplitudes of KvLQT1/minK expressed in CHO cells or in Xenopus oocytes, excluding a direct effect of BRL37344 on the channel. 1 micromol/l BRL37344 mildly prolonged action potentials in guinea pig ventricle (APD(90):+7.8%) CONCLUSIONS: We have demonstrated a functional coupling between the beta(3)-adrenoceptor and ion channel function in the mammalian heart. Our findings point to a potential role for beta(3)-adrenoceptors in cardiac electrophysiology and pathophysiology.

ECG-gated 18F-FDG positron emission tomography.

AIM: 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) provides information about myocardial glucose metabolism to diagnose myocardial viability. Additional information about the functional status is necessary. Comparison of tomographic metabolic PET with data from other imaging techniques is always hampered by some transfer uncertainty and scatter. We wanted to evaluate a new Fourier-based ECG-gated PET technique using a high resolution scanner providing both metabolic and functional data with respect to feasibility in patients with diseased left ventricles. METHODS: Forty-five patients with coronary artery disease and at least one left ventricular segment with severe hypokinesis or akinesis at biplane cineventriculography were included. A new Fourier-based ECG-gated metabolic 18F-FDG-PET was performed in these patients. Function at rest and 18F-FDG uptake were examined in the PET study using a 36-segment model. RESULTS: Segmental comparison with ventriculography revealed a high reliability in identifying dysfunctional segments (> 96%). 18F-FDG uptake of normokinetic/hypokinetic/akinetic segments was 75.4 +/- 7.5, 65.3 +/- 10.5, and 35.9 +/- 15.2% (p < 0.001). In segments > or = 70% 18F-FDG uptake no akinesia was observed. No residual function was found below 40% 18F-FDG uptake. An additional dobutamine test was performed and revealed inotropic reserve (viability) in 42 akinetic segments and 45 hypokinetic segments. CONCLUSION: ECG-gated metabolic PET with pixel-based Fourier smoothing provides reliable data on regional function. Assessment of metabolism and function makes complete judgement of segmental status feasible within a single study without any transfer artefacts or test-to-test variability. The results indicate the presence of considerable amounts of viable myocardium in regions with an uptake of 40-50% 18F-FDG.

[Remodeling in atrial fibrillation]. / Remodeling bei Vorhofflimmern.

BACKGROUND: Atrial fibrillation is associated with alterations in atrial electrophysiology that facilitate the initiation and persistence of the arrhythmia. This process was termed electrical remodeling in atrial fibrillation. The underlying cellular and molecular mechanisms have intensively been investigated over the past few years in patients with atrial fibrillation and in different experimental models. The results, that have substantially improved the understanding of the pathophysiology of atrial fibrillation, are reviewed. CELLULAR AND MOLECULAR MECHANISMS: On the cellular level, atrial fibrillation leads to a strong shortening and an impaired rate adaptation of the action potential as well as to changes in action potential morphology. Atrial fibrillation is associated with an altered gene expression of the L-type calcium channel (ICa,L) and of potassium channels (Ito, IK1, IKACh). The molecular mechanisms of intraatrial conduction slowing are less well understood, changes in the expression or distribution of gap junction proteins or a decrease of the fast sodium inward channel (INa) have been reported in some studies. A trigger of initiation for electrical remodeling is an overload of the cytoplasm with Ca2+ and a consecutive decrease of the systolic calcium gradient, furthermore changes in calcium-handling proteins are detectable in atrial fibrillation. CONCLUSION: These changes in the cellular and molecular milieu importantly determine the clinical course and the efficacy of therapeutical interventions in atrial fibrillation. The clinical relevance and potential new therapeutic approaches are discussed in the last part.

Comparison of C-reactive protein and terminal complement complex in patients with unstable angina pectoris versus stable angina pectoris.

Elevated C-reactive protein (CRP) can identify patients with coronary artery disease who are prone to future acute events. We investigated whether elevated CRP is related to the activation of the terminal complement cascade in 66 patients with unstable angina pectoris (UAP), in 45 patients with stable angina pectoris, and in 42 controls. CRP, additional acute phase reactants, the terminal complement complex (sC5b-9), leukocytes, and troponin T were measured. In 47 patients with UAP the CRP values were regarded as elevated (>0.3 mg/dl). In patients with UAP and elevated CRP, the plasma levels of sC5b-9 were markedly higher than in patients with UAP and lower CRP (245 +/- 14 vs 188 +/- 19 ng/ml, p <0.02) and in patients with stable angina pectoris with slightly (0.4 +/- 0.1 mg/dl) increased CRP (sC5b-9 173 +/- 21 vs 130 +/- 7 ng/ml [controls; p <0.05]). A further acute phase reaction was present only in patients with UAP and elevated CRP already on admission (p <0.01). sC5b-9 was not related to troponin release. Thus, elevated CRP levels are associated with activation of the plaque destabilizating terminal complement system in patients with UAP during the acute phase reaction. This may explain the prognostic value of CRP in acute coronary syndromes (ACS).

Influence of heart rate on vessel visibility in noninvasive coronary angiography using new multislice computed tomography: experience in 94 patients.

OBJECTIVES: Initial reports indicate that coronary artery lesions might be visualized with high sensitivity and specificity by the use of recently introduced multislice computed tomography (MSCT). Current CT technology offers a temporal resolution of 250 ms. In case of heart rates (HRs) >65 beats/min (bpm), however, the reconstruction software switches from a single-phase algorithm (using data from one heart cycle only) to a biphase algorithm using image data of two consecutive heart cycles, improving temporal resolution to down to 125 ms. Thus, it was the aim of the present study to evaluate the influence of the patients' (pts) HR on image quality expressed by vessel segment visibility. METHODS AND RESULTS: MSCT scans (Somatom VZ) were performed in 94 pts. Ten coronary segments were analyzed in each patient with regard to image quality (RCA: segments [sgts] 1-4, LMS: sgt 5, LAD: sgts 5-8, LCX: sgts 11, 12). A total of 697 of 940 (74.1%) sgts were accurately visualizable (RCA: 244/376 [64.9%], LMS: 94/94 [100%], LAD: 232/283 (82.3%), LCX: 146/188 [77.7%]). Beta-blocker therapy had a significant influence on mean HR (65 pts on beta-blocker, HR 65.1+/-10.7 bpm vs. 29 pts, HR 71.6+/-12.2 bpm, P=.01). A significant inverse correlation between HR and segmental visibility was found (r=-.48, P<.0001), with best visibility in pts with lower HRs (n=14 pts with 10 analyzable sgts, HR 60+/-10.1 vs. n=8 pts with 4 analyzable sgts, HR 79.9+/-6.9, P<.0001). CONCLUSIONS: Our results indicate that vessel visibility is highly dependent on the pts HR. Best vessel visibility was found in pts with HR <65 bpm with single-phase image reconstruction. Thus, it appears to be advisable to evaluate, and if needed, to lower the pts HRs before undergoing MSCT coronary angiography in order to achieve best image quality.

Use of beta-blockers in atrial fibrillation.

Atrial fibrillation is the most common arrhythmia in the general population and is frequently associated with organic heart disease. beta-adrenoceptor antagonists (b-blockers) are very effective in preventing atrial fibrillation after coronary artery bypass surgery. It has been shown recently that the beta-blocker metoprolol controlled release/extended release (CR/XL) is also effective in maintaining sinus rhythm after conversion of atrial fibrillation. There is concern that class I antiarrhythmic drugs, such as quinidine, disopyramide, and flecainide in particular, may increase mortality. The risk of proarrhythmia associated with beta-blocker treatment is very low. Therefore b-blockers, such as metoprolol CR/XL, may be the first line of treatment to maintain sinus rhythm, especially after myocardial infarction and in patients with chronic heart failure and in those with arterial hypertension. In patients with persistent atrial fibrillation, AV-nodal conduction-slowing drugs, such as calcium channel antagonists and beta-blockers are used to control the ventricular rate during atrial fibrillation. Several studies clearly show that beta-blockers alone, or in combination with digoxin are very effective in controlling the ventricular rate at rest and during exercise. beta-blockers are effective in maintaining sinus rhythm and controlling the ventricular rate during atrial fibrillation. Given these effects and their favorable effects on mortality, beta-blockers should be considered as first-line agents in the management of patients with atrial fibrillation.