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Myofiber passive stiffness is lowered by phosphorylation of the giant sarcomeric protein titin, with beneficial effects on diastolic function. Titin can be phosphorylated by cGMP-activated protein kinase (PK)G, a pathway stimulated by B-type natriuretic peptide (BNP) or PDE-5A inhibitor (sildenafil). Whether titin phosphorylation and stiffness are affected by PKG activation in vivo had not been studied. Here we examined how dogs with experimental hypertension and diastolic dysfunction, induced by renal wrapping, respond to treatment with β-blockers, sildenafil, and BNP, in terms of altered titin phosphorylation and passive stiffness. Isolated permeabilized cardiomyocytes from left ventricular (LV) biopsies untreated (n=5), treated with β-blockers (n=7), followed by sildenafil (n=7) and BNP (n=7) were attached to a force transducer and the passive length tension relation (F pas ) was measured between 1.8 and 2.4µm sarcomere length (SL) before and after PKA and PKG administration. We also assessed phosphorylation of myofilament proteins including titin, cMyBPC, desmin, cTnT, cTnI and MLC2 by gel electrophoresis (SYPRO Ruby and ProQ Diamond stain) and expression of titin PEVK, phospho-PEVK, cTnI, phospho-cTnI (at Ser 23/24), PKCα and phospho-PKCα by Western blotting. Compared to untreated cardiomyocytes, F pas was unaltered with β-blocker therapy, but significantly reduced with sildenafil; with BNP F pas did not change further. Ex-vivo administration of PKG lowered F pas of untreated and β-blocker cardiomyocytes to the levels measured in sildenafil and BNP samples, and additional administration of PKA did not further change F pas . Total titin phosphorylation was low in untreated samples and with β-blockade, but significantly increased with sildenafil and BNP. Total cTnI phosphorylation and phospho-cTnI at Ser 23/24 were low in untreated compared to treated samples but were similar between β-blocker, sildenafil and BNP groups. Phospho-PEVK and phospho-PKCα were high in untreated samples and with β-blockade, but reduced with sildenafil and BNP. Acute cGMP enhancing therapy with sildenafil and BNP improves LV diastolic function through correction of a titin phosphorylation deficit, thereby reducing cardiomyocyte passive stiffness.

Introduction: Advanced age is a risk factor for poor outcomes following left ventricular assist device (LVAD) implant. A means of identifying elderly patients with acceptable mortality risk following LVAD surgery is not currently available. The HeartMate II (HMII) Risk Score (HMRS) was recently developed and validated, providing good risk discrimination for predicting survival in patients undergoing HMII implant. Independent survival predictors in the model included age and markers of renal function, coagulopathy and nutrition. We hypothesize that the HMRS will provide utility for risk stratification of the elderly LVAD candidate. Methods: Elderly patients (age >65 years) enrolled into the HMII Destination Therapy (DT) and Bridge to Transplant trials were selected for the study (n=444). Complete data for HMRS calculation was available in 98% (n=435). Preoperative patient HMRS was calculated according to the formula: HMRS = ln(1.29)*decade of age + ln(0.71)*Albumin + ln(1.37)*Cr + ln(1.86)*INR + ln(0.52)*LVAD Center Volume >=15 + ln(0.67)*Implant after 2007. Patients were trichotimized into high (HMRS >1.0), medium (HMRS 0.50-1.0), and low (HMRS <=0.50) risk categories (as previously defined in model development) based on HMRS. The primary endpoint was survival at 1 year following LVAD implant, estimated using Kaplan-Meier methods. Results: The mean cohort age was 71±4 years and 84% (n=372) had devices implanted for DT. The table shows the HMRS along with mean±stddev values for the score's components. All between-group differences were statistically significant (Kruskal-Wallis p<0.05), although differences in age were not clinically significant. Survival based on HMRS strata is shown in the figure. Patients in the low and medium risk groups had survivals >80% at 1 year following LVAD implant. Conclusions: The HMRS can be used to identify elderly patients with survivals comparable to that of the general LVAD population.

Background: In peripheral artery disease (PAD), claudication limits exercise performance, functional status and quality of life. Phosphodiesterase III inhibitors improve claudication-limited exercise performance in patients with PAD. K-134, a novel phosphodiesterase III inhibitor, was evaluated in a phase II trial incorporating an adaptive design to assess safety, quality of life and peak walking time (PWT) on a graded treadmill with cilostazol as an active comparator. Design: Patients with PAD were randomized to receive placebo (N = 87), K-134 at a dose of 25 mg (N = 42), 50 mg (N = 85) or 100 mg (N = 84), or cilostazol at a dose of 100 mg (N = 89), each given twice daily for 26 weeks. A Data Safety Monitoring Board (DSMB) implemented adaptive design was used to allow early discontinuation of unsafe or minimally informative K-134 arms. Interim safety assessments at 2 weeks included dosing of study medication at the study site followed by measurements of postural vital signs and symptoms, and at 4 weeks with a treadmill test at peak drug concentration to evaluate for ischemia or arrhythmias. Results: Based on prospectively defined adaptive criteria, the 25 mg K-134 arm was discontinued as the 50 mg and 100 mg doses were adequately tolerated, had no unanticipated safety signals, and were thus most likely to be informative concerning K-134 in the target population. In the intention-to-treat cohorts at 26 weeks PWT increased by 37% in the 100 mg K-134 arm and 23% on placebo (primary analysis p = 0.089). Using a mixed effects analysis in the entire population, 100 mg K-134 and cilostazol were each superior to placebo in improving PWT. In the per protocol population both K-134 100 mg and cilostazol 100 mg increased PWT as compared with placebo at 14 and 26 weeks. K-134 had tolerability and adverse effect profiles similar to that of cilostazol, with gastrointestinal adverse events, headache and dizziness the most common. Both drugs were associated with an increase in withdrawals prior to study completion due to adverse events as compared with placebo. Conclusions: K-134 was generally well tolerated, and at a dose of 100 mg twice daily had a safety profile and effect on treadmill walking performance that was similar to that of cilostazol.

Introduction: Cardiac veins serve as substrate for arrhythmogenesis, and are especially involved as foci in atrial fibrillation. Understanding cardiac vein anatomy along with myocardial extension into these structures can improve electrophysiological mapping and electrical isolation of arrhythmogenic substrate. Accurately defining cardiac vein anatomy is critical in improving success of ablation therapy for atrial fibrillation. Methods: We performed measurements on 620 formalin-fixed autopsy hearts explanted from October 1998 to July 2003. The integrity of the thoracic veins and their cardiac connections were examined and systematic measurements of the superior and inferior vena cavae, azygous vein, vein of Marshall, coronary sinus, and pulmonary veins were performed and data were analyzed using univariate statistics. Results: We found that muscular extensions into the pulmonary veins were visible in 99% of the examined hearts, and were circumferential around the vein ostia (99.6%). Muscle extension into the SVC was found in 78% of examined hearts. These extensions were largely circumferential around the ostium (39%), but were also found to be asymmetric in a majority of hearts. Asymmetry was found in hearts with longer muscle extensions; no symmetry was observed in extensions greater than 0.8cm. Muscle extensions into the IVC were not seen. Occasionally, macroscopic muscle extensions into the azygous vein were visible (6%). The vein of Marshall was found to be patent to probing in the majority of hearts examined (72%) and was almost always overlying the lateral left atrial endocardial ridge. Conclusions: Our data suggest that all pulmonary veins need to be electrically isolated during atrial fibrillation ablation because of the almost universal presence of myocardial tissue extending into the veins. Mapping of the SVC should be done circumferentially and if potentials are noted isolation should also be performed. The IVC did not have muscle extensions and is unlikely to be a site of arrhythmogenesis. The azygous vein occasionally had muscle extensions and thus requires mapping and possible isolation. The vein of Marshall can be a substrate for arrhythmogenesis and is accessible for ablation by targeting the lateral left atrial endocardial ridge.

Background: Recent case series and smaller registries from around the world have reported higher frequency of Takotsubo Cardiomyopathy (TTC) in females.The aim of this study was to look for gender difference and age - gender interactions for TTC across the nation. Methods: This was a cross sectional study using the Nationwide Inpatient Sample (NIS) 2007 database. TTC or Broken heart syndrome or Reversible left ventricular dysfunction following sudden emotional stress or Stress induced Cardiomyopathy or Transient left ventricular apical ballooning syndrome was defined as patients discharged with any ICD code of 429.83 ( http://www.cdc.gov/nchs/data/icd9/agendasept05.pdf ). Multivariate logistic regression with interaction variable between age and sex was performed. Results: There were 6229 estimated discharges in 2007 NIS. Of these, 5558 (89.2 %) were females and 671 (10.8%) were males. 11.1 % were between 18-50 years, 32% between 50-65 years,58% were more than 65 years. Overall females had significantly higher odds of developing TTC (OR, 7.5; 95% CI, 6.31-9.13). In age group > 55yrs, the odds of developing TTC was 9.5 times higher in females than in males, while in age 55yrs had 2.9 times higher odds of developing TTC while there was no such age difference in males. Conclusions: We conclude that women have 7.5 times higher odds of developing TTC than males. Females with age > 55 years have 2.9 times higher odds of developing TTC than females with age < 55 years. Further research needs to be done on hormonal influence and its effect on TTC.

Introduction- Recent studies based on echocardiographic data have described an entity termed paradoxical low-flow, low-gradient severe aortic stenosis (AS) with preserved ejection fraction (EF). It is not clear whether this condition is also seen in patients who undergo hemodynamic catheterization. Objective- To determine the prevalence of low-flow in patients with low mean gradient (MG) severe AS despite preserved EF as determined by echocardiography who subsequently undergo hemodynamic catheterization. Methods- We retrospectively reviewed medical records of 259 patients who underwent hemodynamic catheterization at Mayo Clinic from 2000-2009 to assess the severity of AS within 6 months of their echocardiographic study. Results- A total of 35 patients (mean age 75±9yrs; 49% males) had MG (≤ 40 mm Hg) and aortic valve area (AVA ≤ 1 cm2) despite preserved EF (≥50%) as determined by echocardiography. A total of 7/35 patients (20%) had low flow by echocardiography, defined as stroke volume index (SVI) ≤ 35 ml/m2 (median SVI of 32 ml/m2, inter-quartile range 30-33 ml/m2). Among the same 35 patients, there were 23 patients who had both low MG (≤ 40 mm Hg) and severe AS (AVA ≤ 1 cm2), while a total of 14/35 patients (40%) had low MG, severe AS as well as low flow (median SVI of 32 ml/m2, inter-quartile range 29-33 ml/m2) as determined by hemodynamic catheterization. A statistically significant correlation with modest association was observed between invasive and noninvasive measurements of MG, SVI, and AVA (r=0.48 ; p = 0.003; r=0.48; p = 0.004 ; r=0.36; p=0.03 respectively) in our study group of 35 patients. In most patients (94%) MG by catheterization was also ≤ 40 mm Hg. However, agreement between echocardiography and catheterization to identify patients with paradoxical low-flow, low MG, severe AS was poor (kappa = 0.03). Conclusions- 1) Paradoxical low flow, low-gradient severe aortic stenosis is also observed in patients who undergo hemodynamic catheterization. 2) Further studies are needed to better understand the pathophysiology, best method for diagnosis and true prevalence of this entity.

Introduction: Creation of an atrial septal defect via atrial septostomy (AS) is a therapeutic option traditionally utilized for PAH in settings where medical therapy was unavailable. Its utility in the context of progressive disease despite medical therapy remains incompletely understood. Hypothesis: AS may be a useful option in patients with symptomatic PAH despite medical therapy and may improve functional class. Methods: Single center retrospective study of all adult PAH patients receiving AS at a tertiary PAH referral center. Results: Eleven atrial septostomy procedures were performed in 8 patients who were refractory to maximal medical management. All patients were WHO functional class III or IV and average patient age was 40 ± 13 years with a female predominance (89%). Mean RA pressure was 18 ± 4 mm Hg with cardiac index of 2.28 ± 0.82 L/min/m 2 prior to AS. Mean pulmonary artery pressure was 63 mm Hg with a pulmonary artery saturation of 48% and average systolic blood pressure of 97 mm Hg. Baseline NT-proBNP was 5573 ± 4589 pg/ml with a mean 6 minute walk distance (6MWD) of 311 ± 131 meters. Five of the 11 procedures resulted in functional class improvement. Functional class change did not relate to change in 6MWD or NT-pro BNP level. Three patients had repeat AS due to spontaneous narrowing of the original septostomy, with a mean duration of 220 ± 135 days between procedures. One patient died within 30 days of the procedure and another at day 88 while one patient received a heart/lung transplant at day 42 post AS. Mean follow up was 243 ± 183 days. The REVEAL risk scores ranged from 10 to 15, with predicted 1 year survival from pre-septostomy clinical data ranging from 22% to 80% (mean predicted survival of 57%). Actual transplant free survival at 1 year was 63%. Conclusions: Selected patients at high risk for 1 year mortality may receive symptomatic benefit from atrial septostomy. One year mortality remains high, and not significantly different from that predicted by the REVEAL score. Atrial septostomy may be a palliative treatment option for patients who are refractory to maximal medical therapy but further long term investigation is necessary.

Aortic stenosis (AS) requires repeat assessments to optimally time intervention. The utility of laboratory tests to complement clinical and hemodynamic assessments has not been established. We assessed clinical, echocardiographic, and laboratory data in 76 patients with AS or heart valve replacement (HVR), age 77 years, 37% women. Laboratory assessments included von Willebrand factor (VWF) antigen, activity, (Act/Ag, normal > 0.8), VWF multimer distribution (abnormal=loss of highest molecular weight multimers=Mult+), brain natriuretic peptide (BNP, abnormal > 155 pg/ml=BNP+), and platelet function analyzer 100 collagen-ADP closure time (PFA, normal < 121 seconds). Table: Coefficients of correlation, r, and F statistic. Chi-square, and probability. Correlation of BNP to mean gradient in patients with GFR>60 remained poor, r=0.29, while for PFA r = 0.65. Median (IQR) for PFA and BNP for mild, moderate, and severe AS and HVR are shown below. VWF multimers were abnormal in 3/14 mild AS, 6/14 moderate AS, 22/25 severe AS and 4/23 HVR patients. The severity of AS was most strongly associated with VWF multimer abnormality and prolonged PFA closure time, weakly with BNP, and not with VWF Act/Ag. Conclusion: Among various laboratory measures, PFA and VWF multimers are strongly associated with AS severity, and may merit assessment as complementary diagnostic and prognostic biomarkers in AS.

Purpose: We previously analyzed the 2006 appropriateness criteria for cardiac computed tomography (CT) and found 42% of our patients were not classifiable, suggesting the criteria were difficult to apply clinically. These criteria were revised in 2010. The purpose of our study is to compare the new 2010 appropriate use criteria to the original 2006 criteria to determine if the 2010 criteria were more applicable. Materials and Methods: In a previous study we applied the 2006 appropriateness criteria to 251 patients that underwent cardiac CT from June 1 to December 31, 2007. Each patient was assigned an indication from the 2006 appropriate use criteria by two observers, classifying patients as appropriate, inappropriate, uncertain, or nonclassifiable. A third observer settled disagreements. This process was applied to the same 251 patients using the 2010 criteria. The data from the previous study using the 2006 criteria was compared to the data obtained using the 2010 criteria to determine changes in the number of nonclassifiable, appropriate, inappropriate, and uncertain exams. These results were then analyzed using Bowker's test of symmetry. Observer agreement was calculated using the kappa statistic. Results: 115 patients (46%) were not classifiable using the 2006 criteria. When the 2010 criteria were applied, the number of not classifiable patients decreased to 40 (16%), with the plurality, 41 (16%), of the not classifiable patients moving to inappropriate. In 2006, 69 (27%) were classified as appropriate, 25 (10%) were uncertain, 42 (17%) inappropriate. In 2010, the appropriate increased to 84 (33%), uncertain increased to 40 (16%), and inappropriate increased to 87 (35%). Bowker's test of symmetry demonstrated a statistically significant change with a p<0.001. Agreement between the two observers assigning patients to classification groups also improved with a kappa of 0.55 using the 2010 criteria compared to kappa of 0.31 in 2006. Conclusion: The number of not classifiable patients decreased using the 2010 criteria and the interobserver agreement improved, suggesting they are more applicable and complete than the 2006 criteria. This decrease in not classifiable patients came primarily from an increase in the number of inappropriate indications.

Implantable cardioverter-defibrillator (ICD) therapy in children and congenital heart disease (CHD) patients is hampered by poor long-term lead survival. Lead extraction is technically difficult and carries substantial morbidity. Manufacturers developed distinct strategies for this issue: thinner lead bodies or a Gore ePTFE coil coating. Both design changes were thought to improve ease of lead removal, but have not been directly compared in children or adults. The purpose of this study was to assess thin and ePTFE-coated ICD lead survival in pediatric and CHD pts. Methods: The Pediatric Lead Extractability and Survival Evaluation (PLEASE) Study began as a Phase IV multicenter open-label prospective study [ NCT00335036 ], facilitated by the Pediatric & Congenital EP Society. Initially designed as a randomized study, it changed to a parallel assignment registry when 1 lead had an advisory due to high incidence of failure, prompting concern about continued clinical equipoise. Pediatric and CHD pts who underwent ICD lead implant from 2005-2010 were eligible. The end date was NCDR ICD Registry v2.0 release (includes pediatric & lead data). 23 centers participated; each site obtained IRB approval. De-identified data was sent to the PI center for verification and statistical analyses. Results: A total of 982 ICD pts (357 VVI, 558 DDD, 67 CRT-D) entered the PLEASE study, incl. 423 pts (43%) with CHD. Mean age at implant = 18.3 ± 9.9 yrs. Thin (< 7Fr) ICD leads accounted for 51%, 23% were ePTFE-coated, 26% neither thin nor coated. There were 113 ICD lead failures (11.5%) at a mean lead-age of 2.2 ± 1.7 yrs, causing shocks in 55 pts. Failure occurred in 21% of thin leads vs 3.5% of ePTFE leads (p<0.01). Extraction was performed on 142 (14.5%) leads overall; 21% of thin leads (incl. extraction of 29 functioning leads due to recall) vs. 4.4% of ePTFE leads (p<0.01). There were 7 major extraction complications (4.9%), but no procedural mortality. Among thin leads, 90/270 (33.3%) of recalled leads failed vs 15/229 (6.6%) non-recalled thin leads. Conclusions: This Phase IV study demonstrates that ICD leads in children and CHD pts have suboptimal performance overall. Thinner leads were much more likely to fail and/or be extracted compared with ePTFE leads, chiefly driven by one lead type.