Circulating S-Glutathionylated cMyBP-C as a Biomarker for Cardiac Diastolic Dysfunction.

Background cMyBP-C (Cardiac myosin binding protein-C) regulates cardiac contraction and relaxation. Previously, we demonstrated that elevated myocardial S-glutathionylation of cMyBP-C correlates with diastolic dysfunction (DD) in animal models. In this study, we tested whether circulating S-glutathionylated cMyBP-C would be a biomarker for DD. Methods and Results Humans, African Green monkeys, and mice had DD determined by echocardiography. Blood samples were acquired and analyzed for S-glutathionylated cMyBP-C by immunoprecipitation. Circulating S-glutathionylated cMyBP-C in human participants with DD (n=24) was elevated (1.46±0.13-fold, P=0.014) when compared with the non-DD controls (n=13). Similarly, circulating S-glutathionylated cMyBP-C was upregulated by 2.13±0.47-fold (P=0.047) in DD monkeys (n=6), and by 1.49 (1.22-2.06)-fold (P=0.031) in DD mice (n=5) compared with the respective non-DD controls. Circulating S-glutathionylated cMyBP-C was positively correlated with DD in humans. Conclusions Circulating S-glutathionylated cMyBP-C was elevated in humans, monkeys, and mice with DD. S-glutathionylated cMyBP-C may represent a novel biomarker for the presence of DD.

Cardiac Resynchronization and Circulating Markers of Sarcoplasmic Reticulum Calcium Handling and Sudden Death Risk.

Cardiac resynchronization therapy (CRT) can improve heart function and decrease arrhythmic events. We tested whether CRT altered circulating markers of calcium handling and sudden death risk. Circulating cardiac sodium channel messenger RNA (mRNA) splicing variants indicate arrhythmic risk, and a reduction in sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) is thought to diminish contractility in heart failure. CRT was associated with a decreased proportion of circulating, nonfunctional sodium channels and improved SERCA2a mRNA expression. Patients without CRT did not have improvement in the biomarkers. These changes might explain the lower arrhythmic risk and improved contractility associated with CRT.

Obstructive Sleep Apnea and Circulating Potassium Channel Levels.

BACKGROUND: Cardiac arrhythmias and sudden cardiac death are more frequent in patients with obstructive sleep apnea (OSA). OSA is associated with QT prolongation, and QT prolongation is an independent risk factor for sudden cardiac death. Because QT prolongation can be mediated by potassium channel loss of function, we tested whether OSA or continuous positive airway pressure therapy altered mRNA expression of circulating white blood cell potassium channels. METHODS AND RESULTS: In total, 28 patients with OSA newly diagnosed by polysomnogram and 6 participants without OSA were enrolled. Potassium channel levels in white blood cells at baseline and at a 4-week follow-up visit were compared. There was a significant inverse correlation between the severity of the OSA stratified by apnea-hypopnea index and mRNA expression of the main potassium channels assessed: KCNQ1 (r=-0.486, P=0.007), KCNH2 (r=-0.437, P=0.016), KCNE1 (r=-0.567, P=0.001), KCNJ2 (r=-0.442, P=0.015), and KCNA5 (r=-0.468, P=0.009). In addition, KCNQ1, KCNH2, and KCNE1 inversely correlated with the oxygen desaturation index 4. After 4 weeks of continuous positive airway pressure therapy, circulating KCNQ1 and KCNJ2 were increased 1.4±0.4-fold (P=0.040) and 2.1±1.4-fold (P=0.046) in the moderate OSA group. Compared with patients with mild or moderate OSA, patients with severe OSA had a persistently higher apnea-hypopnea index (mild 2.0±1.8, moderate 1.0±0.9, severe 5.8±5.6; P=0.015), perhaps explaining why the potassium channel changes were not seen in the severe OSA group. CONCLUSIONS: The mRNA expression of most potassium channels inversely correlates with the severity of OSA and hypoxemia. Continuous positive airway pressure therapy improves circulating KCNQ1 and KCNJ2 in patients with moderate OSA.

Biventricular defibrillator patients have higher complication rates after revision of recalled leads.

BACKGROUND: Since the 2009 revised advisory statement regarding Sprint Fidelis® Defibrillator Lead failure rates (Medtronic Inc., Minneapolis, MN, USA), there has been a significant increase in revision of these leads. We sought to establish the frequency of major procedural complications and determine what patient characteristics were associated with these outcomes. METHODS: We retrospectively reviewed the charts of 621 patients with Fidelis® leads being followed in the University of Pittsburgh Medical Center through January 1, 2010. The population was then examined for rates of lead malfunction, revision, and complication. RESULTS: The average time from implantation of Fidelis® lead to endpoint was 32 ± 16 months. Overall lead survival rates were 89% at 41 months and were lower in biventricular implantable cardioverter defibrillator (BiVICD) as compared to standard implantable cardioverter defibrillator patients (log rank P = 0.053). Prophylactic revisions increased dramatically during 2009 (9.4% vs 1.4%, P < 0.001). Among the 131 patients who underwent revision during the entire time of follow-up, 11 patients had postoperative complications (8.5%). The only significant variable found between patients who did and did not have complications was the presence of a BiVICD (81.8 vs 48.7%, P = 0.036). Of the 40 total patients who underwent lead extraction, all three complications occurred in patients with BiVICDs. CONCLUSION: The number of prophylactic Fidelis® lead revisions has increased dramatically since 2008, and procedure-related complications have been higher than anticipated. Major procedural complication rates are greater among patients with BiVICDs. Overall, lead extraction does not appear to increase procedural risk as compared to abandonment.