Background-The extent of the peri-infarct zone by magnetic resonance imaging (MRI) has been related to all-cause mortality in patients with coronary artery disease. This relationship may result from arrhythmogenesis in the infarct border. However, the relationship between tissue heterogeneity in the infarct periphery and arrhythmic substrate has not been investigated. In the present study, we quantify myocardial infarct heterogeneity by contrast-enhanced MRI and relate it to an electrophysiological marker of arrhythmic substrate in patients with left ventricular (LV) systolic dysfunction undergoing prophylactic implantable cardioverter defibrillator placement. Methods and Results-Before implantable cardioverter defibrillator implantation for primary prevention of sudden cardiac death, 47 patients underwent cine and contrast-enhanced MRI to measure LV function, volumes, mass, and infarct size. A method for quantifying the heterogeneous infarct periphery and the denser infarct core is described. MRI indices were related to inducibility of sustained monomorphic ventricular tachycardia during electrophysiological or device testing. For the noninducible versus inducible patients, LV ejection fraction (30Ϯ10% versus 29Ϯ7%, Pϭ0.79), LV end-diastolic volume (220Ϯ70 versus 228Ϯ57 mL, Pϭ0.68), and infarct size by standard contrast-enhanced MRI definitions (PϭNS) were similar. Quantification of tissue heterogeneity at the infarct periphery was strongly associated with inducibility for monomorphic ventricular tachycardia (noninducible versus inducible: 13Ϯ9 versus 19Ϯ8 g, Pϭ0.015) and was the single significant factor in a stepwise logistic regression. Conclusions-Tissue heterogeneity is present and quantifiable within human infarcts. More extensive tissue heterogeneity correlates with increased ventricular irritability by programmed electrical stimulation. These findings support the hypothesis that anatomic tissue heterogeneity increases susceptibility to ventricular arrhythmias in patients with prior myocardial infarction and LV dysfunction.

Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-β, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-β signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. Mitral valves from fibrillin-1-deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-β activation and signaling. In addition, TGF-β antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-β-related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease. IntroductionMarfan syndrome (MFS) is a common, autosomal-dominant, systemic disorder of connective tissue, with an estimated prevalence of 1 in 5,000-10,000 individuals (1). It is caused by mutations in FBN1, the gene encoding fibrillin-1 (2), the principal component of extracellular matrix microfibrils. Clinical manifestations of MFS include skeletal deformities, ocular lens dislocation, lung pathology, and cardiac complications, such as aortic dissection and mitral valve prolapse (MVP) and dysfunction. Mitral valve disease is the leading indication for surgery and cause of death in young children with MFS, and there are currently no known or proposed medical therapies for prophylactic treatment of valve disease. While infants presenting with the most severe and rapidly progressive form of MFS can show mitral valve dysfunction at birth, manifestations are highly variable in the classic form of MFS, and myxomatous changes are not easily quantified using noninvasive imaging modalities, precluding a precise understanding of the natural history of disease. To our knowledge, neither recapitulation nor mechanistic exploration of mitral valve pathology in mouse models of MFS has previously been documented.

BACKGROUND Infections after placement of cardiac implantable electronic devices (CIEDs) are associated with substantial morbidity and mortality. There is limited evidence on prophylactic strategies, other than the use of preoperative antibiotics, to prevent such infections. METHODS We conducted a randomized, controlled clinical trial to assess the safety and efficacy of an absorbable, antibiotic-eluting envelope in reducing the incidence of infection associated with CIED implantations. Patients who were undergoing a CIED pocket revision, generator replacement, or system upgrade or an initial implantation of a cardiac resynchronization therapy defibrillator were randomly assigned, in a 1:1 ratio, to receive the envelope or not. Standard-of-care strategies to prevent infection were used in all patients. The primary end point was infection resulting in system extraction or revision, long-term antibiotic therapy with infection recurrence, or death, within 12 months after the CIED implantation procedure. The secondary end point for safety was procedure-related or system-related complications within 12 months. RESULTS A total of 6983 patients underwent randomization: 3495 to the envelope group and 3488 to the control group. The primary end point occurred in 25 patients in the envelope group and 42 patients in the control group (12-month Kaplan-Meier estimated event rate, 0.7% and 1.2%, respectively; hazard ratio, 0.60; 95% confidence interval [CI], 0.36 to 0.98; P = 0.04). The safety end point occurred in 201 patients in the envelope group and 236 patients in the control group (12-month Kaplan-Meier estimated event rate, 6.0% and 6.9%, respectively; hazard ratio, 0.87; 95% CI, 0.72 to 1.06; P<0.001 for noninferiority). The mean (±SD) duration of follow-up was 20.7±8.5 months. Major CIED-related infections through the entire follow-up period occurred in 32 patients in the envelope group and 51 patients in the control group (hazard ratio, 0.63; 95% CI, 0.40 to 0.98). CONCLUSIONS Adjunctive use of an antibacterial envelope resulted in a significantly lower incidence of major CIED infections than standard-of-care infection-prevention strategies alone, without a higher incidence of complications. (Funded by Medtronic; WRAP-IT ClinicalTrials.gov number, NCT02277990.).

No abstract

Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-β, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-β signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. Mitral valves from fibrillin-1-deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-β activation and signaling. In addition, TGF-β antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-β-related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease. IntroductionMarfan syndrome (MFS) is a common, autosomal-dominant, systemic disorder of connective tissue, with an estimated prevalence of 1 in 5,000-10,000 individuals (1). It is caused by mutations in FBN1, the gene encoding fibrillin-1 (2), the principal component of extracellular matrix microfibrils. Clinical manifestations of MFS include skeletal deformities, ocular lens dislocation, lung pathology, and cardiac complications, such as aortic dissection and mitral valve prolapse (MVP) and dysfunction. Mitral valve disease is the leading indication for surgery and cause of death in young children with MFS, and there are currently no known or proposed medical therapies for prophylactic treatment of valve disease. While infants presenting with the most severe and rapidly progressive form of MFS can show mitral valve dysfunction at birth, manifestations are highly variable in the classic form of MFS, and myxomatous changes are not easily quantified using noninvasive imaging modalities, precluding a precise understanding of the natural history of disease. To our knowledge, neither recapitulation nor mechanistic exploration of mitral valve pathology in mouse models of MFS has previously been documented.

Complication rates from AF ablation remain significant, despite improved techniques and increased awareness of procedural risks. Both advanced age and female gender predict major adverse events, suggesting careful consideration of the risk/benefit profile in these patients prior to ablation.

Despite oral anticoagulation treatment, there is a small but significant incidence of LA thrombus by TEE prior to AF ablation. A CHADS(2) score >or= 2 and larger LA diameter are independent predictors of LA thrombus in this patient population, while type of AF or rhythm at the time of TEE is not. The risk of LA thrombus is low in patients with a CHADS(2) score of 0 and in patients with an LA diameter < 4.5 cm.

Background-The risks of sports participation for implantable cardioverter-defibrillator (ICD) patients are unknown. Methods and Results-Athletes with ICDs (age, 10-60 years) participating in organized (n=328) or high-risk (n=44) sports were recruited. Sports-related and clinical data were obtained by phone interview and medical records. Follow-up occurred every 6 months. ICD shock data and clinical outcomes were adjudicated by 2 electrophysiologists. Median age was 33 years (89 subjects <20 years of age); 33% were female. Sixty were competitive athletes (varsity/junior varsity/traveling team). A pre-ICD history of ventricular arrhythmia was present in 42%. Running, basketball, and soccer were the most common sports. Over a median 31-month (interquartile range, 21-46 months) follow-up, there were no occurrences of either primary end point-death or resuscitated arrest or arrhythmia-or shock-related injury-during sports. There were 49 shocks in 37 participants (10% of study population) during competition/practice, 39 shocks in 29 participants (8%) during other physical activity, and 33 shocks in 24 participants (6%) at rest. In 8 ventricular arrhythmia episodes (device defined), multiple shocks were received: 1 at rest, 4 during competition/practice, and 3 during other physical activity. Ultimately, the ICD terminated all episodes. Freedom from lead malfunction was 97% at 5 years (from implantation) and 90% at 10 years. Conclusions-Many athletes with ICDs can engage in vigorous and competitive sports without physical injury or failure to terminate the arrhythmia despite the occurrence of both inappropriate and appropriate shocks. These data provide a basis for more informed physician and patient decision making in terms of sports participation for athletes with ICDs.