Coronary heart disease and its main complication, myocardial infarction is leading cause of death worldwide. Over the past years, much progress has been made in the pharmacotherapy of major risk ...factors like dyslipidemias, diabetes mellitus and hypertension. The targeting of coronary risk factors coupled with advances in the management of coronary artery disease has improved patient survival. However, the incidence of cardiovascular disease is projected to continue to rise and the identification of individuals at risk should improve beyond the traditional models of global risk factor scoring. In the past few years, important progresses have been made in the area of genomics, especially with the completion of the human genome-sequencing Consortium of 2004, proteomics and imaging. This progress will promote a better understanding of cardiovascular risk assessments and disease prediction, thus allowing earlier preventive strategies to prevent and improve cardiovascular outcomes. These genomic advances have improved characterization of disease pathology especially at the molecular level with the discovery and introduction of genetic markers, single nucleotide polymorphisms (SNPs), and haplotype blocks.
Abstract Recent reports have highlighted the importance of a family history of sudden death as a risk for ventricular fibrillation (VF) in patients experiencing acute myocardial infarction (AMI), ...pointing to the possibility of a genetic predisposition. This report briefly reviews 2 recent studies designed to examine the hypothesis that there is a genetic predisposition to the development of arrhythmias associated with AMI. Ventricular tachycardia and VF (VT/VF) complicating AMI as well as arrhythmias associated with Brugada syndrome, a genetic disorder linked to SCN5A mutations, have both been linked to phase 2 reentry. Because of these mechanistic similarities in arrhythmogenesis, we examined the contribution of SCN5A mutations to VT/VF complicating AMI in patients developing VF during AMI. A missense mutation in SCN5A was found in a patient who developed an arrhythmic electrical storm during an evolving myocardial infarction. All VT/VF episodes were associated with ST-segment changes and were initiated by short-coupled extrasystoles. G400A mutation and H558R polymorphism were on the same allele, and functional expression in TSA201 demonstrated loss of function of sodium channel activity. These results suggest that a subclinical mutation in SCN5A resulting in a loss of function may predispose to life-threatening arrhythmias during acute ischemia. In another cohort of patients who developed long-QT intervals and torsade de pointes arrhythmias in days 2 to 11 after an AMI, a genetic screening of all long-QT genes was performed. Of 8 patients in this group, 6 (75%) displayed the same polymorphism in KCNH2, which encodes the α -subunit of the rapidly activating delayed rectifier potassium current, IKr . The K897T polymorphism was detected in only 3 of 14 patients with uncomplicated myocardial infarction and has been detected in 33% of the white population. Expression of this polymorphism has previously been shown to cause a loss of function in HERG current consistent with the long-QT phenotype. These observations suggest a genetic predisposition to the development of long-QT intervals and torsade de pointes in the days after an AMI. These preliminary studies provide support for the hypothesis that there is a genetic predisposition to the type and severity of arrhythmias that develop during and after an AMI, and that additional studies are warranted.
Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.
This study sought to perform a retrospective ...analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.
Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.
A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.
This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.
Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of ...these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG.
Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers.
We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
BACKGROUND—The Brugada syndrome, an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in 4 different genes, leading to a loss of function in ...sodium and calcium channel activity. Although the transient outward current (Ito) is thought to play a prominent role in the expression of the syndrome, mutations in Ito-related genes have not been identified as yet.
METHODS AND RESULTS—One hundred five probands with the Brugada syndrome were screened for ion channel gene mutations using single-strand conformation polymorphism electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in 1 proband. The R99H mutation was found 4/4 phenotype-positive and 0/3 phenotype-negative family members. Chinese hamster ovary-K1 cells were cotransfected using wild-type (WT) or mutant KCNE3 and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and KCNE3 were analyzed in coimmunoprecipitation experiments in human atrial samples. Cotransfection of R99H-KCNE3 with KCNQ1 produced no alteration in tail current magnitude or kinetics. However, cotransfection of R99H KCNE3 with KCND3 resulted in a significant increase in the Ito intensity compared with WT KCNE3+KCND3. Using tissues isolated from the left atrial appendages of human hearts, we also demonstrate that Kv4.3 and KCNE3 can be coimmunoprecipitated.
CONCLUSIONS—These results provide definitive evidence for a functional role of KCNE3 in the modulation of Ito in the human heart and suggest that mutations in KCNE3 can underlie the development of the Brugada syndrome.
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.
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.
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.
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).
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).
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