Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment ...elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death.
Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca(v beta2b)), CACNA2D1 (Ca(v alpha2delta1)), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca(v)1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals < or = 360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the alpha1- and beta2b-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca(v)1.2 channels but normal trafficking of channels containing G490R Ca(v)1.2 or S481L Ca(v beta2b)-subunits.
This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.
L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC ...mutations contribute to the J-wave syndromes associated with sudden cardiac death.
The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Ca(v)1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing.
Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval.
The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca(v) genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.
D-dimers have been discovered as by-products of fibrinolysis. In situations where the fundamental pathology is associated with increased thrombolytic activity, D-dimer assays could serve an integral ...role in the clinical workup, and have an already established role in the diagnosis of clinical disorders of venous thromboembolism, and disseminated intravascular coagulation. However, there is growing literature suggesting that this is not the only clinical scenario where D-dimers may be of significance. They may also become an important biomarker in coronary and carotid artery atherosclerosis and aortic diseases. Being a non-invasive and quick means of diagnosis, D-dimers are a cost-effective tool used for diagnosing diseases. With the future being steered in the direction of preventive cardiology, it is imperative for clinicians to understand how to effectively utilize biomarkers in order to diagnose disorders. In this context, we review D-dimer's origin, current clinical utility, and potential future applications.
Objectives Our aim was to study the impact of delay from symptom onset to first coronary device on infarct size and clinical outcomes at 30 days and 1 year in patients with ST-segment elevation ...myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. Background Longer delay from symptom onset to reperfusion has been linked to increased mortality and worse clinical outcome. The mechanisms underpinning this association are not entirely clear. Methods The INFUSE-AMI trial (INFUSE-Anterior Myocardial Infarction) randomized patients with anterior STEMI undergoing primary percutaneous coronary intervention with bivalirudin anticoagulation within 5 h of symptom onset to intralesion (IL) bolus abciximab versus no abciximab and to thrombus aspiration versus no aspiration. The primary endpoint was contrast magnetic resonance infarct size (IS) (percentage of left ventricular mass) at 30 days. Time to reperfusion was classified as <3 versus ≥3 h. Results There were 280 patients (62%) with <3-h delay and 170 patients (38%) with ≥3-h delay. Patients with longer delay were significantly older, more often women, and diabetic. Earlier reperfusion was not associated with higher rates of final Thrombolysis In Myocardial Infarction flow grade 3 or myocardial blush grade 2/3, but was an independent predictor of smaller IS (p = 0.02 by multivariable linear regression). Mortality at 1 year was reduced in patients with shorter delay to reperfusion (4.0% vs. 9.2%, p = 0.02). Conclusions In patients with large anterior myocardial infarction undergoing relatively early reperfusion, longer delays to reperfusion were associated with larger IS and 1-year mortality, but not with reduced reperfusion success. (The INFUSE - Anterior Myocardial Infarction AMI Study; NCT00976521 )
Background Both ST-segment resolution (STR) and myocardial blush grade (MBG) have prognostic utility after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction. We ...sought to clarify how frequently MBG and STR provide discordant measures of reperfusion success and to determine the independent prognostic significance of each on long-term outcomes. Methods In HORIZONS-AMI, core laboratory measures of both MBG and STR were assessed in 2,367 patients undergoing primary PCI. Four groups were identified based on MBG (grades 2/3 vs 0/1) and STR (≥50% vs <50%). A multivariable model identified predictors of death and major adverse cardiac events at 3 years. Results Myocardial blush grade 2/3 was achieved in 77.7% of patients, and STR ≥50% was achieved in 75.1% of patients. Myocardial blush grade and STR were discordant in 765 patients (30.9%). By multivariable analysis, MBG 2/3 compared with 0/1 was an independent predictor of lower mortality at 3 years (4.4% vs 8.4%, adjusted hazard ratio HR = 0.57 0.39, 0.82, P = .003). In contrast, STR ≥50% compared with <50% was not associated with mortality (5.1% vs 5.9%, adjusted HR = 1.11 0.68, 1.56, P = .89). However, repeated revascularization at 3 years was less frequent when STR ≥50% (12.4% vs 17.6%, adjusted HR = 0.74 0.58, 0.95, P = .02). In contrast, MBG 2/3 vs 0/1 was not associated with reduced repeated revascularization (13.6% vs 14.1%, adjusted HR = 1.02 0.79, 1.33, P = .85). Conclusions In HORIZONS-AMI, MBG and STR after primary PCI were concordant in only 70% of patients and provided complementary prognostic information. Myocardial blush grade predicted long-term survival, whereas STR predicted freedom from repeated revascularization.
The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and ...is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease. However, the value of the test remains controversial.
We studied 147 individuals representing 4 large families with SCN5A mutations. Of these, 104 were determined to be at possible risk for Brugada syndrome and underwent both electrocardiographic and genetic evaluation. Twenty-four individuals displayed an ECG diagnostic of Brugada syndrome at baseline. Of the remaining, 71 received intravenous ajmaline. Of the 35 genetic carriers who received ajmaline, 28 had a positive test and 7 a negative ajmaline test. The sensitivity, specificity, and positive and negative predictive values of the drug challenge were 80% (28:35), 94.4% (34:36), 93.3% (28:30), and 82.9% (34:41), respectively. Penetrance of the disease phenotype increased from 32.7% to 78.6% with the use of sodium channel blockers. In the absence of ST-segment elevation under baseline conditions, a prolonged P-R interval, but not incomplete right bundle-branch block or early repolarization patterns, indicates a high probability of an SCN5A mutation carrier.
In families with Brugada syndrome, the data suggest that ajmaline testing is valuable in the diagnosis of SCN5A carriers. In the absence of ST-segment elevation at baseline, family members with first-degree atrioventricular block should be suspected of carrying the mutation. An ajmaline test is often the key to making the proper diagnosis in these patients.
Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of cardiovascular morbidity and mortality. Among the gene defects previously associated with AF is a gain of function ...of the slowly activating delayed rectifier potassium current IKs, secondary to mutations in KCNQ1. Coexpression of KCNE5, the gene encoding the MiRP4 beta-subunit, has been shown to reduce IKs.
The purpose of this study was to test the hypothesis that mutations in KCNE5 are associated with AF in a large cohort of patients with AF.
One-hundred fifty-eight patients with AF were screened for mutations in the coding region of KCNE5.
A missense mutation involving substitution of a phenylalanine for leucine at position 65 (L65F) was identified in one patient. This patient did not have a history of familial AF, and neither KCNQ1 nor KCNE2 mutations were found. Transient transfection of Chinese hamster ovary (CHO) cells expressing IKs(KCNQ1+KCNE1) with KCNE5 suppressed the developing and tail currents of IKs in a concentration-dependent manner. Transient transfection with KCNE5-L65F failed to suppress IKs, yielding a current indistinguishable from that recorded in the absence of KCNE5. Developing currents recorded during a test pulse to +60 mV and tail currents recorded upon repolarization to -40 mV both showed a significant concentration-dependent gain of function in IKs with expression of KCNE5-L65F vs KCNE5-WT.
The results of this study suggest that a missense mutation in KCNE5 may be associated with nonfamilial or acquired forms of AF. The arrhythmogenic mechanism most likely is a gain of function of IKs.
Although QT prolongation following myocardial infarction (MI) is generally moderate, cases with marked QT prolongation leading to life-threatening torsades de pointes (TdP) have been described.
To ...investigate the genetic substrate of this phenomenon.
We studied 13 patients who developed TdP in the subacute phase of MI (2-11 days) and a group of 133 ethnically matched controls with uncomplicated MI. Long QT syndrome genes and the KCNH2-K897T polymorphism were screened by using denaturing high-performance liquid chromatography plus direct sequencing and a specific TaqMan assay, respectively.
Two of the 13 patients (15%) who presented with QT prolongation and TdP were found to carry long QT syndrome mutations (KCNH2-R744X and SCN5A-E446K). Nine of the remaining 11 patients (82%) carried the KCNH2-K897T polymorphism, which was present in 35% of the controls (P = .0035). Thus, patients with an acute MI carrying the KCNH2-K897T polymorphism had an 8-fold greater risk of experiencing TdP compared with controls (95% confidence interval = 2-40).
Our data suggest that the common K897T polymorphism is associated with an increased risk of TdP developing in the subacute phase of MI. Our findings support the concept that the electrical remodeling associated with this healing phase of MI may unmask a genetic substrate predisposing to a time-limited development of life-threatening arrhythmias. They also provide the first line of evidence in support of the hypothesis that a common polymorphism, previously described as a modifier of the severity of LQTS, may increase the risk of life-threatening arrhythmias in a much more prevalent cardiac disease such as myocardial infarction.
Rapid reperfusion with primary percutaneous coronary intervention improves survival in patients with ST-segment elevation myocardial infarction. Preprocedural cardiopulmonary instability and adverse ...events (IAE) may delay reperfusion time and worsen prognosis. The aim of this study was to evaluate the relation between preprocedural cardiopulmonary IAE, door-to-balloon time (DBT), and outcomes in the Harmonizing Outcomes With Revascularization and Stents in AMI (HORIZONS-AMI) trial. Preprocedural cardiopulmonary IAE included sustained ventricular or supraventricular tachycardia or fibrillation requiring cardioversion or defibrillation, heart block or bradycardia requiring pacemaker implantation, severe hypotension requiring vasopressors or intra-aortic balloon counterpulsation, respiratory failure requiring mechanical ventilation, and cardiopulmonary resuscitation. Three-year outcomes of patients with and without IAE according to DBT were compared. Among 3,602 patients, 159 (4.4%) had ≥1 IAE. DBT did not differ significantly in patients with and without IAE; however, patients with IAE were less likely to have Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow after percutaneous coronary intervention. Mortality at 3 years was significantly higher in patients with versus those without IAE (17.0% vs 6.3%, p <0.0001), and IAE was an independent predictor of mortality, whereas DBT was not. However, a significant interaction was present such that 3-year mortality was reduced in patients with DBT <99 minutes (the median) versus ≥99 minutes to a greater extent in patients with IAE (9.9% vs 20.7%, hazard ratio 0.43, 95% confidence interval 0.16 to 1.16) compared with those without IAE (5.0% vs 7.2%, hazard ratio 0.69, 95% confidence interval 0.50 to 0.95) (p for interaction = 0.004). In conclusion, IAE before PCI is an independent predictor of death and identifies a high-risk group in whom faster reperfusion may be particularly important to improve survival.
Ventricular tachycardia (VT) and ventricular fibrillation (VF) complicating Brugada syndrome, a genetic disorder linked to SCN5A mutations, and VF complicating acute myocardial infarction (AMI) both ...have been linked to phase 2 reentry.
Given the mechanistic similarities in arrhythmogenesis, the purpose of this study was to examine the contribution of SCN5A mutations to VT/VF complicating AMI.
Nineteen consecutive patients developing VF during AMI were enrolled in the study. Wild-type (WT) and mutant SCN5A genes were coexpressed with SCN1B in TSA201 cells and studied using whole-cell patch clamp techniques.
Among the cohort of 19 patients, one missense mutation (G400A) in SCN5A was detected in a conserved region. An H558R polymorphism was detected on the same allele. Unlike the other 18 patients, who each developed 1-2 VF episodes during AMI, the mutation carrier developed six episodes of VT/VF within the first 12 hours. All VT/VF episodes were associated with ST-segment changes and were initiated by short-coupled extrasystoles. Flecainide and adenosine challenge performed to unmask Brugada and long QT syndromes both were negative. Peak G400A and G400A+H558R current were 70.7% and 88.4% less than WT current at -35 mV (P </=.001). G400A current decay was accelerated and steady-state inactivation was shifted -6.39 mV (V(1/2) = -98.9 +/- 0.1 mV vs -92.5 +/- 0.1 mV, P </=.001). No mutations were detected in KCNH2, KCNQ1, KCNE1, or KCNE2 in the G400A patient.
We describe the first sodium channel mutation to be associated with the development of an arrhythmic storm during acute ischemia. These findings suggest that a loss of function in SCN5A may predispose to ischemia-induced arrhythmic storm.
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