Jan Minners

Small or Large Isolation Areas Around the Pulmonary Veins for the Treatment of Atrial Fibrillation? Results From a Prospective Randomized Study

Background— Pulmonary vein (PV) isolation is a promising new treatment for atrial fibrillation (AF). We hypothesized that isolation of large areas around both ipsilateral PVs with verification of conduction block is more effective than the isolation of each individual PV. Methods and Results— A total of 110 patients, 67 with paroxysmal AF and 43 with persistent AF, were randomly assigned to undergo either isolation of each individual PV or isolation of large areas around both ipsilateral PVs. The isolation of each individual PV was an electrophysiologically guided, ostial segmental ablation with a 64-pole basket catheter or a 20-pole circular mapping catheter (group I). Isolation of large areas was performed around the 2 ipsilateral veins with a nonfluoroscopic navigation system and a circular 20-pole mapping catheter for verification of conduction block (group II). In both groups, an irrigated-tip ablation catheter (25 to 35 W) was used to achieve complete isolation. Procedure and ablation times were longer in group II, whereas fluoroscopic time was significantly shorter (P≤0.001). After a follow-up period of 15±4 months, 27 patients in group I (49%) and 37 patients in group II (67%) remained free of symptoms of AF and had no AF or atrial flutter during repetitive Holter monitoring without antiarrhythmic drug treatment after a single procedure (P≤0.05). Conclusions— The rate of success was significantly higher and fluoroscopy times were significantly lower in the group with large isolation areas around both ipsilateral PVs than in those who underwent individual PV isolation.

Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary Intervention

BACKGROUND Whether bivalirudin is superior to unfractionated heparin in patients with stable or unstable angina who undergo percutaneous coronary intervention (PCI) after pretreatment with clopidogrel is unknown. METHODS We enrolled 4570 patients with stable or unstable angina (with normal levels of troponin T and creatine kinase MB) who were undergoing PCI after pretreatment with a 600-mg dose of clopidogrel at least 2 hours before the procedure; 2289 patients were randomly assigned in a double-blind manner to receive bivalirudin, and 2281 to receive unfractionated heparin. The primary end point was the composite of death, myocardial infarction, urgent target-vessel revascularization due to myocardial ischemia within 30 days after randomization, or major bleeding during the index hospitalization (with a net clinical benefit defined as a reduction in the incidence of the end point). The secondary end point was the composite of death, myocardial infarction, or urgent target-vessel revascularization. RESULTS The incidence of the primary end point was 8.3% (190 patients) in the bivalirudin group as compared with 8.7% (199 patients) in the unfractionated-heparin group (relative risk, 0.94; 95% confidence interval [CI], 0.77 to 1.15; P=0.57). The secondary end point occurred in 134 patients (5.9%) in the bivalirudin group and 115 patients (5.0%) in the unfractionated-heparin group (relative risk, 1.16; 95% CI, 0.91 to 1.49; P=0.23). The incidence of major bleeding was 3.1% (70 patients) in the bivalirudin group and 4.6% (104 patients) in the unfractionated-heparin group (relative risk, 0.66; 95% CI, 0.49 to 0.90; P=0.008). CONCLUSIONS In patients with stable and unstable angina who underwent PCI after pretreatment with clopidogrel, bivalirudin did not provide a net clinical benefit (i.e., it did not reduce the incidence of the composite end point of death, myocardial infarction, urgent target-vessel revascularization, or major bleeding) as compared with unfractionated heparin, but it did significantly reduce the incidence of major bleeding. (ClinicalTrials.gov number, NCT00262054.)

Outcome of Patients With Low-Gradient “Severe” Aortic Stenosis and Preserved Ejection Fraction

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area <1.0 cm2 and mean gradient ⩽40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P<0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (⩽35 mL/m2; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Outcome of Patients With Low-Gradient “Severe” Aortic Stenosis and Preserved Ejection Fraction The Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area <1.0 cm2 and mean gradient ⩽40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P<0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (⩽35 mL/m2; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Inconsistent grading of aortic valve stenosis by current guidelines: haemodynamic studies in patients with apparently normal left ventricular function

Background On echocardiography approximately one-third of patients with severe aortic valve stenosis based on aortic valve area (AVA<1.0 cm2) demonstrate a non-severe mean pressure gradient (ΔPm; ≤40 mm Hg) despite apparently normal left ventricular function. It has been suggested that inconsistent echocardiographic grading may be due to ‘paradoxical’ low stroke volume. However, the correct echocardiographic assessment of stroke volume hinges on the often problematic measurement of the left ventricular outflow tract (LVOT) diameter. Objective To investigate whether inconsistent grading and reduced stroke volume persist when the quantification of aortic valve stenosis is based on cardiac catheterisation which is independent of LVOT measurements. Methods and results 333 consecutive patients underwent cardiac catheterisation within 30 days after their index echocardiography showing an AVA ≤2 cm2 and shortening fraction ≥30%. On invasive testing 85 patients (26%) demonstrated inconsistent (AVA<1 cm2 and ΔPm≤40 mm Hg) and 153 (46%) consistent grading (AVA<1 cm2 and ΔPm>40 mm Hg) with the remainder (28%) presenting with a calculated AVA≥1 cm2. Inconsistently graded patients were older (71 vs 67 years, p<0.006) with no differences in sex or body surface area between groups. Stroke volume and stroke volume index were significantly lower in inconsistently graded patients (63±14 vs 73±18 ml and 35±7 vs 39±7 ml/m2, respectively, both p<0.001). However, 41/85 (48%) of inconsistently graded patients had a normal stroke volume index >35 ml/m2. Conclusion In the framework of current guidelines inconsistent grading of aortic valve stenosis is common, extends to cardiac catheterisation and is only partially explained by low stroke volume despite apparently normal left ventricular systolic function.

Rapid rule out of acute myocardial infarction using undetectable levels of high-sensitivity cardiac troponin

BACKGROUND We examined whether undetectable levels of high-sensitivity cardiac Troponin (hs-cTn) can be used to rule out acute myocardial infarction (AMI) with a single blood draw at presentation to the emergency department (ED). METHODS AND RESULTS In a prospective multicenter study we used 4 different hs-cTn assays (hs-cTnT Roche, and hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting with acute chest pain. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available data including serial hs-cTnT levels. Mean follow up was 24 months. Among 2072 consecutive patients with available hs-cTnT levels, 21% had an adjudicated diagnosis of AMI. Among AMI patients, 98.2% had initially detectable levels of hs-cTnT (sensitivity 98.2%, 95%CI 96.3%-99.2%, negative predictive value (NPV) 98.6%, 95%CI 97.0%-99.3%). Undetectable levels of hs-cTnT ruled out AMI in 26.5% of patients at presentation. The NPV was similar with the three hs-cTnI assays: among 1180 consecutive patients with available hs-cTnI (Siemens), the NPV was 98.8%; among 1151 consecutive patients with available hs-cTnI (Beckman Coulter), the NPV was 99.2%; among 1567 consecutive patients with available hs-cTnI (Abbott), the NPV was 100.0%. The percentage of patients with undetectable levels of hs-cTnI was similar among the three hs-cTnI assays and ranged from 11.4% to 13.9%. CONCLUSIONS Undetectable levels of hs-cTn at presentation have a very high NPV and seem to allow the simple and rapid rule out of AMI. This criteria applies to much more patients with hs-TnT as compared to the investigated hs-cTnI assays.

Pre-ablative predictors of atrial fibrillation recurrence following pulmonary vein isolation: the potential role of inflammation.

AIMS An increasing body of evidence has demonstrated the essential role of inflammation in the genesis and maintenance of atrial fibrillation (AF). The aim of the present study was to investigate whether success or failure of electrical pulmonary vein isolation (PVI) in patients with AF is related with the presence of a pre-ablative inflammatory state as determined by known clinical parameters and conventional markers of inflammation including high-sensitivity C-reactive protein, white blood cell (WBC) count, and fibrinogen. METHODS AND RESULTS Seventy-two patients with paroxysmal (64%) or persistent AF (36%) underwent successful electrical PVI. The mean duration of arrhythmia was 5.5 +/- 2.9 years. After a mean follow-up period of 12.5 +/- 5.7 months, 44 patients (61%) were in sinus rhythm. In univariate Cox proportional hazard regression analysis, hypertension, body mass index (BMI), left ventricular ejection fraction, left ventricular end-diastolic diameter, left atrial diameter (LAD), WBC count, and high-sensitivity C-reactive protein were significantly associated with AF recurrence (P < 0.05). In multivariate Cox proportional hazard regression analysis, hypertension [hazard ratio (HR) 3.127; 95% confidence interval (CI) 1.269-7.706, P = 0.013], LAD (HR 1.077; 95% CI 1.014-1.144, P = 0.015), and WBC count (HR 1.423; 95% CI 1.067-1.897, P = 0.016) were independent pre-ablative predictors of AF recurrence following PVI. CONCLUSION Conventional markers of the inflammatory cascade such as WBC count and high-sensitivity C-reactive protein as well as elements of the metabolic syndrome such as hypertension and increased BMI were significantly associated with AF recurrence. The impact of a pre-ablative inflammatory state in the overall success rate of PVI needs further elucidation.

Ablation of Persistent Atrial Fibrillation Targeting Low-Voltage Areas With Selective Activation Characteristics

Background—Complex-fractionated atrial electrograms and atrial fibrosis are associated with maintenance of persistent atrial fibrillation (AF). We hypothesized that pulmonary vein isolation (PVI) plus ablation of selective atrial low-voltage sites may be more successful than PVI only. Methods and Results—A total of 85 consecutive patients with persistent AF underwent high-density atrial voltage mapping, PVI, and ablation at low-voltage areas (LVA<0.5 mV in AF) associated with electric activity lasting >70% of AF cycle length on a single electrode (fractionated activity) or multiple electrodes around the circumferential mapping catheter (rotational activity) or discrete rapid local activity (group I). The procedural end point was AF termination. Arrhythmia freedom was compared with a control group (66 patients) undergoing PVI only (group II). PVI alone was performed in 23 of 85 (27%) patients of group I with low amount (<10% of left atrial surface area) of atrial low voltage. Selective atrial ablation in addition to PVI was performed in 62 patients with termination of AF in 45 (73%) after 11±9 minutes radiofrequency delivery. AF-termination sites colocalized within LVA in 80% and at border zones in 20%. Single-procedural arrhythmia freedom at 13 months median follow-up was achieved in 59 of 85 (69%) patients in group I, which was significantly higher than the matched control group (31/66 [47%], P<0.001). There was no significant difference in the success rate of patients in group I with a low amount of low voltage undergoing PVI only and patients requiring PVI+selective low-voltage ablation (P=0.42). Conclusions—Ablation of sites with distinct activation characteristics within/at borderzones of LVA in addition to PVI is more effective than conventional PVI-only strategy for persistent AF. PVI only seems to be sufficient to treat patients with left atrial low voltage <10%.

Risk stratification in patients with acute chest pain using three high-sensitivity cardiac troponin assays

AIMS Several high-sensitivity cardiac troponin (hs-cTn) assays have recently been developed. It is unknown which hs-cTn provides the most accurate prognostic information and to what extent early changes in hs-cTn predict mortality. METHODS AND RESULTS In a prospective, international multicentre study, cTn was simultaneously measured with three novel [high-sensitivity cardiac Troponin T (hs-cTnT), Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI, Siemens] and a conventional assay (cTnT, Roche Diagnostics) in a blinded fashion in 1117 unselected patients with acute chest pain. Patients were followed up 2 years regarding mortality. Eighty-two (7.3%) patients died during the follow-up. The 2-year prognostic accuracy of hs-cTn was most accurate for hs-cTnT [area under the receivers operating characteristic curve (AUC) 0.78 (95% CI: 0.73-0.83) and outperformed both hs-cTnI (Beckman-Coulter, 0.71 (95% CI: 0.65-0.77; P = 0.001 for comparison), hs-cTnI (Siemens) 0.70 (95% CI: 0.64-0.76; P < 0.001 for comparison)] and cTnT 0.67 (95% CI: 0.61-0.74; P < 0.001 for comparison). Absolute changes of hs-cTnT were more accurate than relative changes in predicting mortality, but inferior to presentation values of hs-cTnT. Combining changes of hs-cTnT within the first 6 h with their presentation values did not further improve prognostic accuracy. Similar results were obtained for both hs-cTnI assays regarding the incremental value of changes. Hs-cTn concentrations remained predictors of death in clinically challenging subgroups such as patients with pre-existing coronary artery disease, impaired renal function, and patients older than 75 years. CONCLUSION High-sensitivity cardiac Troponin T is more accurate than hs-cTnI in the prediction of long-term mortality. Changes of hs-cTn do not seem to further improve risk stratification beyond initial presentation values.

Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Background—Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program. Methods and Results—Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (P<0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (≥22% versus control, P<0.001). After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191±12% improvement in ADP-sensitive respiration (P=0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator–activated receptor gamma coactivator 1&agr;, were significantly induced in preconditioned myocardium. Conclusions—Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling.