Humberto Vidaillet

Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease

BACKGROUND Inherited mutations cause approximately 35 percent of cases of dilated cardiomyopathy; however, few genes associated with this disease have been identified. Previously, we located a gene defect that was responsible for autosomal dominant dilated cardiomyopathy and conduction-system disease on chromosome 1p1-q21, where nuclear-envelope proteins lamin A and lamin C are encoded by the LMNA (lamin A/C) gene. Mutations in the head or tail domain of this gene cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and in some cases by abnormalities of cardiac conduction during adulthood. METHODS We evaluated 11 families with autosomal dominant dilated cardiomyopathy and conduction-system disease. Sequences of the lamin A/C exons were determined in probands from each family, and variants were confirmed by restriction-enzyme digestion. The genotypes of the family members were ascertained. RESULTS Five novel missense mutations were identified: four in the alpha-helical-rod domain of the lamin A/C gene, and one in the lamin C tail domain. Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy. Heart failure and sudden death occurred frequently within these families. No family members with mutations had either joint contractures or skeletal myopathy. Serum creatine kinase levels were normal in family members with mutations of the lamin rod but mildly elevated in some family members with a defect in the tail domain of lamin C. CONCLUSIONS Genetic defects in distinct domains of the nuclear-envelope proteins lamin A and lamin C selectively cause dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery-Dreifuss muscular dystrophy. Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediate filament protein has an important role in cardiac conduction and contractility.

CYP4F2 genetic variant alters required warfarin dose.

Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450 4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.

Resuscitation Preferences Among Patients With Severe Congestive Heart Failure Results From the SUPPORT Project

BACKGROUND We sought to describe the resuscitation preferences of patients hospitalized with an exacerbation of severe congestive heart failure, perceptions of those preferences by their physicians, and the stability of the preferences. METHODS AND RESULTS Of 936 patients in this study, 215 (23%) explicitly stated that they did not want to be resuscitated. Significant correlates of not wanting to be resuscitated included older age, perception of a worse prognosis, poorer functional status, and higher income. The physicians perception of the patients preference disagreed with the patients actual preference in 24% of the cases overall. Only 25% of the patients reported discussing resuscitation preferences with their physician, but discussion of preferences was not significantly associated with higher agreement between the patient and physician. Of the 600 patients who responded to the resuscitation question again 2 months later, 19% had changed their preferences, including 14% of those who initially wanted resuscitation (69 of 480) and 40% of those who initially did not (48 of 120). The physicians perception of the patients hospital resuscitation preference was correct for 84% of patients who had a stable preference and 68% of those who did not. CONCLUSIONS Almost one quarter of patients hospitalized with severe heart failure expressed a preference not to be resuscitated. The physicians perception of the patients preference was not accurate in about one quarter of the cases. but communication was not associated with greater agreement between the patient and the physician. A substantial proportion of patients who did not want to be resuscitated changed their minds within 2 months of discharge.

A population-based study of mortality among patients with atrial fibrillation or flutter

PURPOSE To determine the mortality associated with atrial flutter and atrial fibrillation in the general population. SUBJECTS AND METHODS Using the Marshfield Epidemiologic Study Area, a database that captures nearly all medical care and deaths among its 58,820 residents, we identified patients diagnosed with atrial flutter or atrial fibrillation from July 1, 1991, through June 30, 1995. Patients were followed prospectively and compared with a group of controls without these arrhythmias. RESULTS A total of 4775 person-years of follow-up were completed in 577 patients and 577 controls. Compared with controls, mortality among patients with atrial fibrillation or flutter was nearly 7.8-fold higher at 6 months (95% confidence interval [CI]: 4.1 to 15) and 2.5-fold higher (95% CI: 2.0 to 3.1; P < 0.0001) at the last follow-up (mean [+/- SD] of 3.6 +/- 2.3 years; range, 1 day to 7.3 years). At 6 months, mortality among patients with atrial flutter alone was somewhat greater than in controls and less than one third that of those with atrial fibrillation (with or without atrial flutter) (P = 0.02). At the last follow-up, however, mortality was greater among patients with atrial flutter (hazard ratio [HR] = 1.7; 95% CI: 1.2 to 2.6; P = 0.007), atrial fibrillation (HR = 2.4; 95% CI: 1.9 to 3.1; P < 0.0001), or both atrial arrhythmias (HR = 2.5; 95% CI: 1.9 to 3.3; P < 0.0001) when compared with controls in models that adjusted for cardiovascular risk factors. CONCLUSION In the general population, both atrial flutter and atrial fibrillation are independent predictors of increased late mortality. The relatively benign course during the 6-month period after the initial diagnosis of atrial flutter suggests that early diagnosis and treatment of these patients may improve their long-term survival.

Gender Differences in Procedure-Related Adverse Events in Patients Receiving Implantable Cardioverter-Defibrillator Therapy

Background— Women are at higher risk than men for adverse events with certain invasive cardiac procedures. Our objective was to compare rates of in-hospital adverse events in men and women receiving implantable cardioverter- defibrillator (ICD) therapy in community practice. Methods and Results— Using the National Cardiovascular Data Registry ICD Registry, we identified patients undergoing first-time ICD implantation between January 2006 and December 2007. Outcomes included in-hospital adverse events after ICD implantation. Multivariable analysis assessed the association between gender and in-hospital adverse events, with adjustment for demographic, clinical, procedural, physician, and hospital characteristics. Of 161 470 patients, 73% were male, and 27% were female. Women were more likely to have a history of heart failure (81% versus 77%, P<0.01), worse New York Heart Association functional status (57% versus 50% in class III and IV, P<0.01), and nonischemic cardiomyopathy (44% versus 27%, P<0.01) and were more likely to receive biventricular ICDs (39% versus 34%, P<0.01). In unadjusted analyses, women were more likely to experience any adverse event (4.4% versus 3.3%, P<0.001) and major adverse events (2.0% versus 1.1%, P<0.001). In multivariable models, women had a significantly higher risk of any adverse event (OR 1.32, 95% CI 1.24 to 1.39) and major adverse events (OR 1.71, 95% CI 1.57 to 1.86). Conclusions— Women are more likely than men to have in-hospital adverse events related to ICD implantation. Efforts are needed to understand the reasons for higher ICD implantation–related adverse event rates in women and to develop strategies to reduce the risk of these events.

Evaluation of genetic factors for warfarin dose prediction.

Objectives: Warfarin is a commonly prescribed anticoagulant drug used to prevent thromboses that may arise as a consequence of orthopedic and vascular surgery or underlying cardiovascular disease. Warfarin is associated with a notoriously narrow therapeutic window where small variations in dosing may result in hemorrhagic or thrombotic complications. To ultimately improve dosing of warfarin, we evaluated models for stable maintenance dose that incorporated both clinical and genetic factors. Method: A model was constructed by evaluating the contribution to dosing variability of the following clinical factors: age, gender, body surface area, and presence or absence of prosthetic heart valves or diabetes. The model was then sequentially expanded by incorporating polymorphisms of cytochrome P450 (CYP) 2C9; vitamin K 2,3 epoxide reductase complex, subunit 1 (VKORC1); gamma carboxylase; factor VII; and apolipoprotein (Apo) E genes. Results: Of genetic factors evaluated in the model, CYP2C9 and VKORC1 each contributed substantially to dose variability, and together with clinical factors explained 56% of the individual variability in stable warfarin dose. In contrast, gamma carboxylase, factor VII and Apo E polymorphisms contributed little to dose variability. Conclusion: The importance of CYP2C9 and VKORC1 to patient-specific dose of warfarin has been confirmed, while polymorphisms of gamma carboxylase, factor VII and Apo E genes did not substantially contribute to predictive models for stable warfarin dose.

Cost-effectiveness of rhythm versus rate control in atrial fibrillation.

Context Randomized trials show that rate control and rhythm control are similarly effective in the treatment of atrial fibrillation; therefore, economic issues will play a large role in the choice of therapy. Contribution This cost-effectiveness model shows that rate control saves costs compared with rhythm control. Implications From an economic perspective, unless specific clinical factors suggest a benefit of rhythm control for a particular patient, rate control seems to be the preferred strategy for the management of atrial fibrillation. Atrial fibrillation is the most common sustained type of cardiac arrhythmia treated by physicians. Its prevalence increases with advancing age, affecting approximately 5% of those 65 years of age and older and 10% of those older than 80 years of age (1-3). As the U.S. population ages, it is expected that more than 5 million persons will be living with atrial fibrillation by the year 2050 (4). Despite significant advances in the effectiveness of treatments for atrial fibrillation and its associated comorbid conditions, disability and mortality from atrial fibrillation remain high (5-10). The optimal approach to the rhythm management of atrial fibrillation remains unclear. There are 2 main approaches: Rhythm control uses electrical cardioversion, antiarrhythmic drugs, and, sometimes, nonpharmacologic therapies (for example, multisite atrial pacing, maze procedures, or radiofrequency ablation procedures) to maintain sinus rhythm; rate control uses atrioventricular nodal blocking agents (and, if needed, ablation of the atrioventricular junction and pacemaker implantation) for ventricular rate control. Recently, several randomized, controlled studies have compared rate control versus rhythm control. In the largest of these studies, investigators in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) randomly assigned 4060 patients with atrial fibrillation (mean age, 70 years) to either rate control or rhythm control (10-12). After a mean follow-up of 3.5 years, mortality did not differ significantly between the groups (hazard ratio for rate control vs. rhythm control, 0.87 [95% CI, 0.75 to 1.01]; P= 0.08), and the rate-control approach was associated with a lower risk for adverse drug effects (12). The results of the other large study were consistent with these findings (13). The RAte Control versus Electrical cardioversion for persistent atrial fibrillation (RACE) study randomly assigned 522 patients with persistent atrial fibrillation after electrical cardioversion to either rhythm control or rate control; the mean follow-up was 2.3 years (13). Patients in both treatment groups received oral anticoagulant drugs. There was a nonsignificant trend toward reduced death or other serious cardiovascular events in patients treated by the rate-control strategy. Consequently, economic factors often play a substantial role in guiding treatment selection. Several authors have examined the incremental cost-effectiveness of rhythm-control versus rate-control strategies for treating atrial fibrillation; however, their studies have been confined to modeling exercises of hypothetical scenarios that lack data on efficacy and resource use from randomized trials (14, 15). This paper reports an economic analysis based on the results of AFFIRM. The objective was to estimate the incremental cost-effectiveness of rhythm-control versus rate-control strategies from AFFIRM. Methods AFFIRM Study Sample AFFIRM included 4060 patients with atrial fibrillation whose treatment was block randomized by center to be either rhythm control or rate control (12). Similar to patients with atrial fibrillation in the general population, most of the patients in AFFIRM were older men (men represented 61% of the sample) with common associated cardiovascular comorbid conditions (history of hypertension [71%], coronary artery disease [39%], and congestive heart failure [9%]). The mean age (SD) for all patients was 69.7 9.0 years, and 75% were 65 years of age or older. The qualifying event was the first episode of atrial fibrillation in 34% of patients and recurrent atrial fibrillation in the remaining 66% of patients. The overriding principles for enrollment of patients in AFFIRM were based on the clinical judgment of the investigator and were as follows: Atrial fibrillation was likely to be recurrent, atrial fibrillation was likely to cause morbidity or death, long-term treatment for atrial fibrillation was warranted, anticoagulation was not contraindicated, the patient was eligible for at least 2 drug trials in both treatment strategies, and treatment in both strategies could be initiated immediately after randomization. Additional information on the design, inclusion and exclusion criteria, and results of AFFIRM are available elsewhere (10-12). The economic analysis described here compares costs and effects of the 2 management strategies among patients enrolled in AFFIRM from the perspective of a third-party payer. The outcome was the incremental cost-effectiveness ratio comparing rhythm control and rate control, measured in dollars per life-year gained. Survival We obtained data on survival from the time of randomization to the end of study follow-up and use of specific health care resources for all 4060 AFFIRM patients. For patients who were lost to follow-up, withdrew from the study, or had incomplete follow-up, all available data were included in the analysis. Patients were censored at withdrawal or loss to follow-up. We derived the within-study mean survival time for each treatment group by using the KaplanMeier product limit estimator to account for censoring during follow-up (16). To obtain an unbiased estimate of mean survival, exposure was truncated at 5.65 years, which was the longest follow-up observed in AFFIRM (17). Resource Use and Costs We estimated costs by multiplying the number of each resource used by its unit cost (18). All unit costs for resources were estimated in U.S. dollars for the year 2002. Price estimates from earlier years were adjusted by applying the Consumer Price Index, Medical Care component (19). For each measure of resource use, 3 different unit costs were derived and considered in separate analyses: a base case for the most likely scenario, a low estimate, and a high estimate. The analysis considered costs of all hospitalizations, cardiac procedures, cardioversion, short-stay and emergency department visits, and medications used to treat atrial fibrillation from the perspective of a third-party payer. Hospital Costs At each follow-up visit during the study, the total number of hospitalized days since the last visit was recorded, along with the primary reason (cardiovascular or noncardiovascular cause) for hospitalization. The mean cost per hospital day was estimated from the Healthcare Cost and Utilization Project (HCUP) statistics for the 1995 HCUP-3 Nationwide Inpatient Sample (20) for Diseases of the Circulatory System, excluding any diagnosis associated with a mean patient age of younger than 18 years, for cardiovascular and noncardiovascular causes. The low and high estimates of the per diem for hospital days were based on the 25th and 75th percentile of mean charges, respectively. The HCUP prices were adjusted to represent costs by using a cost-to-charge ratio of 0.575, which is based on the 2002 estimate from the Centers for Medicare & Medicaid Services (21). In addition, physician charges for subsequent hospital care as a level II visit (Current Procedural Terminology [CPT] [22] code 99232) were applied for each hospital day recorded. In the base case, an average estimate for the physician fee payment for this CPT code was calculated from the 2002 Physician Fee Schedule Payment Amount File National/Carrier for facility-based procedures for all carriers and localities listed in the database (23). In the sensitivity analysis, we used the minimum physician fee across carriers and localities for each procedure as the low cost estimate. We based the high cost estimate on the standard billed charge from the Marshfield Clinic, an ambulatory care facility in Marshfield, Wisconsin. This clinical center recruited most patients in the study and provides an estimate of charges for centers in the United States. Although these estimates are based on data from 1 facility, they are a reasonable estimate for the high-cost scenario, in between billed charges from a teaching hospital and a private clinic. Costs of Cardiac Procedures At each follow-up visit during the study, the number of cardiac procedures (percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, pacemakers, valve surgery, ablation) performed since the previous follow-up visit was recorded. No information was available from AFFIRM to describe the number of arteries revascularized during percutaneous transluminal coronary angioplasty interventions or coronary artery bypass graft surgeries. We assumed that only 1 lesion was treated for each percutaneous transluminal coronary angioplasty procedure. We estimated the number of arteries revascularized during bypass surgery as a weighted average from the National Hospital Discharge Survey (NHDS) data set for 2000 (24, 25). We included the costs of the most frequent cardiac procedures in the analysis. Hospital costs include the costs of all facility personnel except physicians. Physician costs consisted of a physician fee for diagnostic and therapeutic procedures, as well as any applicable anesthesia fee. Perfusionist fees for open-heart cardiac procedures were not included because these costs are included in the hospital costs. The analysis included costs for pacemakers and implantable cardioverter defibrillators (ICDs) because they have high unit cost (24, 25). In the base case, the hardware cost (that is, device and electrode or electrodes costs) for the most widely used single-chamber and dual-chamber device was assigned on the

Familial Occurrence of Accessory Atrioventricular Pathways (Preexcitation Syndrome)

Accessory atrioventricular pathways, the anatomical structures responsible for the preexcitation syndromes, may result from a developmental failure to eradicate the remnants of the atrioventricular connections present during cardiogenesis. To study whether preexcitation syndromes could also be transmitted genetically, we determined the prevalence of preexcitation in the first-degree relatives of 383 of 456 consecutive patients (84 percent) with electrophysiologically proved accessory pathways. We compared the observed prevalence of preexcitation among the 2343 first-degree relatives with the frequency reported in the general population (0.15 percent). For 13 of the 383 index patients (3.4 percent), accessory pathways were documented in one or more first-degree relatives. At least 13 of the 2343 relatives identified (0.55 percent) had preexcitation; this prevalence was significantly higher than that in the general population (P less than 0.0001). Identification of affected relatives may have been incomplete because clinical information was obtained only about symptomatic relatives. Patients with familial preexcitation have a higher incidence of multiple accessory pathways and possibly an increased risk of sudden cardiac death. Our data suggest a hereditary contribution to the development of accessory pathways in humans. The pattern of inheritance appears to be autosomal dominant.

Race, resource use, and survival in seriously III hospitalized adults

OBJECTIVE: To examine the association between patient race and hospital resource use.DESIGN: Prospective cohort study.SETTING: Five geographically diverse teaching hospitals.PATIENTS: Patients were 9,105 hospitalized adults with one of nine illnesses associated with an average 6-month mortality of 50%.MEASUREMENTS AND MAIN RESULTS: Measures of resource use included: a modified version of the Therapeutic Intervention Scoring System (TISS); performance of any of any of five procedures (operation, dialysis, pulmonary artery catheterization, endoscopy, and bronchoscopy); and hospital charges, adjusted by the Medicare cost-to-charge ratio per cost center at each participating hospital. The median patient age was 65; 79% were white, 16% African-American, 3% Hispanic, and 2% other races; 47% died within 6 months. After adjusting for other sociodemographic factors, severity of illness, functional status, and study site, African-Americans were less likely to receive any of five procedures on study day 1 and 3 (adjusted odds ratio [OR] 0.70; 95% confidence interval [CI] 0.60, 0.81). In addition, African-Americans had lower TISS scores on study day 1 and 3 (OR −1.8; 95% CI −1.3, −2.4) and lower estimated costs of hospitalization (OR −

Infections with Nonthoracotomy Implantable Cardioverter Defibrillators: Can These Be Prevented?

2,805; 95% CI −