Dual AV Nodal Nonreentrant Tachycardia Resulting in Inappropriate ICD Therapy in a Patient with Cardiac Sarcoidosis.

Dual atrioventricular nodal nonreentrant tachycardia (DAVNNT) occurs due to concurrent antegrade conduction over fast and slow atrioventricular nodal pathways and is treated by slow pathway modification. We describe a unique case of a patient with cardiac sarcoidosis who received inappropriate ICD shocks for DAVNNT. Atrial and ventricular device electrograms satisfied both rate and V>A criteria for ventricular tachycardia. We postulate that alterations in refractoriness and conduction as is seen in cardiac sarcoidosis (CS) may have contributed to occurrence of DAVNNT.

Oxidative posttranslational modifications mediate decreased SERCA activity and myocyte dysfunction in Galphaq-overexpressing mice.

BACKGROUND: Myocyte contractile dysfunction occurs in pathological remodeling in association with abnormalities in calcium regulation. Mice with cardiac myocyte-specific overexpression of Galphaq develop progressive left ventricular failure associated with myocyte contractile dysfunction and calcium dysregulation. OBJECTIVE: We tested the hypothesis that myocyte contractile dysfunction in the Galphaq mouse heart is mediated by reactive oxygen species, and in particular, oxidative posttranslational modifications, which impair the function of sarcoplasmic reticulum Ca2+-ATPase (SERCA). METHODS AND RESULTS: Freshly isolated ventricular myocytes from Galphaq mice had marked abnormalities of myocyte contractile function and calcium transients. In Galphaq myocardium, SERCA protein was not altered in quantity but displayed evidence of oxidative cysteine modifications reflected by decreased biotinylated iodoacetamide labeling and evidence of specific irreversible oxidative modifications consisting of sulfonylation at cysteine 674 and nitration at tyrosines 294/295. Maximal calcium-stimulated SERCA activity was decreased 47% in Galphaq myocardium. Cross-breeding Galphaq mice with transgenic mice that have cardiac myocyte-specific overexpression of catalase (a) decreased SERCA oxidative cysteine modifications, (b) decreased SERCA cysteine 674 sulfonylation and tyrosine 294/295 nitration, (c) restored SERCA activity, and (d) improved myocyte calcium transients and contractile function. CONCLUSIONS: In Galphaq-induced cardiomyopathy, myocyte contractile dysfunction is mediated, at least in part, by 1 or more oxidative posttranslational modifications of SERCA. Protein oxidative posttranslational modifications contribute to the pathophysiology of myocardial dysfunction and thus may provide a target for therapeutic intervention.

P-wave indices, distribution and quality control assessment (from the Framingham Heart Study).

BACKGROUND: P-wave indices of maximum P-wave duration and P-wave dispersion have been examined in a broad array of cardiovascular and noncardiovascular disease states. The P-wave indices literature has been highly heterogeneous in measurement methodologies, described quality control metrics, and distribution of values. We therefore sought to determine the reproducibility of P-wave indices in a community-based cohort. METHODS: P-wave indices were measured in sequential subjects enrolled in the Framingham Heart Study. Electrocardiograms were obtained at the 11th biennial visit of the Original Cohort (n = 250) and the initial visit of the Offspring Cohort (n = 252). We determined the mean P-wave durations, interlead correlations, and P-wave indices. We then chose 20 ECGs, 10 from each cohort, and assessed intrarater and interrater variability. RESULTS: The maximum P-wave duration ranged from 71 to 162 ms with mean of 112 + or - 12 ms. The minimum P-wave duration ranged from 35 to 103 ms with mean of 65 + or - 10 ms. P-wave dispersion ranged from 12 to 82 ms. The mean P-wave dispersion was 48 + or - 12 ms (40-56). The intrarater intraclass correlation coefficient (ICC) was r = 0.80 for maximum P-wave duration and r = 0.82 for P-wave dispersion. The interrater ICC was 0.56 for maximum P-wave duration and 0.70 for P-wave dispersion. CONCLUSIONS: We demonstrated excellent intrarater reproducibility and fair interrater reproducibility for calculating P-wave indices. Reproducibility is frequently lacking in studies of P-wave indices, but is an essential component for the field's growth and epidemiologic contribution.

Effect of an American Heart Association Get With the Guidelines program-based clinical pathway on referral and enrollment into cardiac rehabilitation after acute myocardial infarction.

Cardiac rehabilitation (CR)/secondary prevention programs are an important part of patient care after acute myocardial infarction (AMI). However, only 10% to 15% of eligible patients enroll in such programs. The purpose of this study was to evaluate the effect of an American Heart Association Get With the Guidelines (GWTG)-based clinical pathway on referral and enrollment into CR after AMI. Patients (n = 780) admitted to a single center during an 18-month period with AMI and discharged to home were evaluated retrospectively for referral and enrollment into CR programs. A total of 714 patients (92%) were on the GWTG pathway; 392 (55%) were referred and 135 (19%) were enrolled into CR. Higher referral was associated with pathway use (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.1 to 4.9, p = 0.03), percutaneous coronary intervention (OR 3.1, 95% CI 1.9 to 5.2, p <0.0001), and in-patient physical therapy consultation (OR 13, 95% CI 8.2 to 20.5, p <0.0001). Ethnicity did not affect referral, but was the only variable associated with lower enrollment. Hispanic and black patients had 92% (OR 0.08, 95% CI 0.01 to 0.55, p = 0.02) and 57% (OR 0.43, 95% CI 0.19 to 1.05, p = 0.06) lower odds to enroll compared with white patients, respectively. In conclusion, use of the American Heart Association GWTG pathway showed a significantly higher referral rate to CR after AMI than previously reported in the literature. Nonetheless, most referred patients did not enroll. Strategies to bridge the gap between referral and enrollment in CR should be incorporated into AMI clinical pathways, with special emphasis on increasing enrollment in ethnic minorities.

TXNIP regulates peripheral glucose metabolism in humans.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. METHODS AND FINDINGS: We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. CONCLUSIONS: TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.

Proatherogenic pathways leading to vascular calcification.

Cardiovascular disease is the leading cause of morbidity and mortality in the western world and atherosclerosis is the major common underlying disease. The pathogenesis of atherosclerosis involves local vascular injury, inflammation and oxidative stress as well as vascular calcification. Vascular calcification has long been regarded as a degenerative process leading to mineral deposition in the vascular wall characteristic for late stages of atherosclerosis. However, recent studies identified vascular calcification in early stages of atherosclerosis and its occurrence has been linked to clinical events in patients with cardiovascular disease. Its degree correlates with local vascular inflammation and with the overall impact and the progression of atherosclerosis. Over the last decade, diverse and highly regulated molecular signaling cascades controlling vascular calcification have been described. Local and circulating molecules such as osteopontin, osteoprogerin, leptin and matrix Gla protein were identified as critical regulators of vascular calcification. We here review the current knowledge on molecular pathways of vascular calcification and their relevance for the progression of cardiovascular disease.

Pharmacotherapy for atrial arrhythmias: present and future.

Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice. It is associated with significant morbidity, including palpitations, exercise intolerance, congestive heart failure, and increased risk of embolic stroke. Mortality is increased twofold in patients with AF. Management of AF with antiarrhythmic drugs traditionally has been hindered by lack of efficacy, poor tolerance of side effects, drug-associated toxicity, and proarrhythmic potential. Improved understanding of atrial electrical and structural remodeling as well as advances in rational drug design have led to new agents that may be superior to their predecessors. New agents that target atrium-specific ion channels limit the potential for ventricular arrhythmias, and less toxic derivatives such as dronedarone may be more tolerable. Drugs with entirely novel mechanisms, such as the gap junction modulator rotigaptide, have shown efficacy in ventricular arrhythmias and have potential for atrial arrhythmias as well. This review discusses recent advances in pharmacotherapy for treatment of atrial arrhythmias.