Development of a biomarker panel to predict cardiac resynchronization therapy response: Results from the SMART-AV trial.

BACKGROUND: Predicting a favorable cardiac resynchronization therapy (CRT) response holds great clinical importance. OBJECTIVE: The purpose of this study was to examine proteins from broad biological pathways and develop a prediction tool for response to CRT. METHODS: Plasma was collected from patients before CRT (SMART-AV [SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy] trial). A CRT response was prespecified as a ≥15-mL reduction in left ventricular end-systolic volume at 6 months, which resulted in a binary CRT response (responders 52%, nonresponders 48%; n = 758). RESULTS: Candidate proteins (n = 74) were evaluated from the inflammatory, signaling, and structural domains, which yielded 12 candidate biomarkers, but only a subset of these demonstrated predictive value for CRT response: soluble suppressor of tumorgenicity-2, soluble tumor necrosis factor receptor-II, matrix metalloproteinase-2, and C-reactive protein. These biomarkers were used in a composite categorical scoring algorithm (Biomarker CRT Score), which identified patients with a high/low probability of a response to CRT (P <.001) when adjusted for a number of clinical covariates. For example, a Biomarker CRT Score of 0 yielded 5 times higher odds of a response to CRT compared to a Biomarker CRT Score of 4 (P <.001). The Biomarker CRT Score demonstrated additive predictive value when considered against a composite of clinical variables. CONCLUSION: These unique findings demonstrate that developing a biomarker panel for predicting individual response to CRT is feasible and holds potential for point-of-care testing and integration into evaluation algorithms for patients presenting for CRT.

Drug-Induced QTc Prolongation.

QTc prolongation has a high prevalence of and is associated with increased all-cause mortality. Nonetheless, QTc prolonging medications are often used during patient hospitalizations despite baseline prolongation and QTc changes. Data regarding the real-world relative risk of QTc prolongation in the hospital setting are lacking. In this study, we sought to quantify the degree and relative risk of QTc prolongation in patients receiving Arizona Center for Education and Research on Therapeutics (AzCERT) "known risk" medications. Electronic medical records of patients receiving an electrocardiogram at the University of Chicago, admitted in 2011 were analyzed. The longest QTc interval and medications administered within the preceding 24 hours were evaluated. Medications were classified into 4 categories according to the AzCERT classification. Of a total of 14,804 patients, mean QTc intervals were 485 versus 454 ms for men and 469 versus 453 ms for women receiving known risk medications compared with those receiving no risk medications (p <0.001). The rate of QTc prolongation was 71% versus 48% for men and 50% versus 34% for women, respectively. There was no significant increase in QTc prolongation for patients administered multiple QT-relevant medications or for those administered only conditional or possible risk medications. In conclusion, the prevalence of significant QTc prolongation in patients receiving AzCERT known risk medications is high. This may be a reflection of inadequate awareness or overall quality inadequacies.

Improved detection of myocardial damage in sarcoidosis using longitudinal strain in patients with preserved left ventricular ejection fraction.

BACKGROUND: Cardiac infiltration is an important cause of death in sarcoidosis. Transthoracic echocardiography (TTE) has limited sensitivity for the detection of cardiac sarcoidosis (CS). Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) is used to diagnose CS but has limitations of cost and availability. We sought to determine whether TTE-derived global longitudinal strain (GLS) may be used to identify individuals with CS, despite preserved left ventricular ejection fraction (LVEF), and whether abnormal GLS is associated with major cardiovascular events (MCE). METHODS: We studied 31 patients with biopsy-proven extra-cardiac sarcoidosis, LVEF>50% and LGE on CMR (CS+ group), and 31 patients without LGE (CS- group), matched by age, sex, and severity of lung disease. GLS was measured using vendor-independent speckle tracking software. Parameters of left and right ventricular systolic and diastolic function were also studied. Receiver-operating characteristic curves were used to identify GLS cutoff for CS detection, and Kaplan-Meier plots to determine the ability of GLS to predict MCE. RESULTS: LGE was associated with reduced GLS (-19.6±1.9% in CS- vs -14.7±2.4% in CS+, P<.01) and with reduced E/A ratio (1.1±0.3 vs 0.9±0.3, respectively, P =.01). No differences were noted in other TTE parameters. GLS magnitude inversely correlated with LGE burden (r=-.59). GLS cutoff of -17% showed sensitivity and specificity 94% for detecting CS. Patients who experienced MCE had worse GLS than those who did not (-13.4±0.9% vs -17.7±0.4%, P=.0003). CONCLUSIONS: CS is associated with significantly reduced GLS in the presence of preserved LVEF. GLS measurements may become part of the TTE study performed to screen for CS.

Cost-effectiveness of implantable cardiac devices in patients with systolic heart failure.

OBJECTIVE: To evaluate the cost-effectiveness of implantable cardioverter defibrillators (ICDs), cardiac resynchronisation therapy pacemakers (CRT-Ps) and combination therapy (CRT-D) in patients with heart failure with reduced ejection fraction based on a range of clinical characteristics. METHODS: Individual patient data from 13 randomised trials were used to inform a decision analytical model. A series of regression equations were used to predict baseline all-cause mortality, hospitalisation rates and health-related quality of life and device-related treatment effects. Clinical variables used in these equations were age, QRS duration, New York Heart Association (NYHA) class, ischaemic aetiology and left bundle branch block (LBBB). A UK National Health Service perspective and a lifetime time horizon were used. Benefits were expressed as quality-adjusted life-years (QALYs). Results were reported for 24 subgroups based on LBBB status, QRS duration and NYHA class. RESULTS: At a threshold of £30 000 per QALY gained, CRT-D was cost-effective in 10 of the 24 subgroups including all LBBB morphology patients with NYHA I/II/III. ICD is cost-effective for all non-NYHA IV patients with QRS duration <120 ms and for NYHA I/II non-LBBB morphology patients with QRS duration between 120 ms and 149 ms. CRT-P was also cost-effective in all NYHA III/IV patients with QRS duration >120 ms. Device therapy is cost-effective in most patient groups with LBBB at a threshold of £20 000 per QALY gained. Results were robust to altering key model parameters. CONCLUSIONS: At a threshold of £30 000 per QALY gained, CRT-D is cost-effective in a far wider group than previously recommended in the UK. In some subgroups ICD and CRT-P remain the cost-effective choice.

Long-Term Success of Irrigated Radiofrequency Catheter Ablation of Sustained Ventricular Tachycardia: Post-Approval THERMOCOOL VT Trial.

BACKGROUND: Radiofrequency catheter ablation is used to treat recurrent ventricular tachycardia (VT). OBJECTIVES: This study evaluated long-term safety and effectiveness of radiofrequency catheter ablation using an open-irrigated catheter. METHODS: Patients with sustained monomorphic ventricular tachycardia associated with coronary disease were analyzed for cardiovascular-specific adverse events within 7 days of treatment, hospitalization duration, 6-month sustained monomorphic ventricular tachycardia recurrence, quality of life measured by the Hospital Anxiety and Depression Scale, long-term (1-, 2-, and 3-year) survival, symptomatic VT control, and amiodarone use. RESULTS: Overall, 249 patients, mean age 67.4 years, were enrolled. The cardiovascular-specific adverse events rate was 3.9% (9 of 233) with no strokes. Noninducibility of targeted VT was achieved in 75.9% of patients. Post-ablation median hospitalization was 2 days. At 6 months, 62.0% (114 of 184) of patients had no sustained monomorphic ventricular tachycardia recurrence; the proportion of patients with implantable cardioverter-defibrillator shocks decreased from 81.2% to 26.8% (p < 0.0001); the frequency of VT in implantable cardioverter-defibrillator patients with recurrences was reduced by ≥50% in 63.8% of patients; and the proportion with normal Hospital Anxiety and Depression Scale scores increased from 48.8% to 69.1% (p < 0.001). Patient-reported VT remained steady for 1, 2, and 3 years at 22.7%, 29.8%, and 24.1%, respectively. Amiodarone use and hospitalization decreased from 55% and 77.2% pre-ablation to 23.3% and 30.7%, 18.5% and 36.7%, 17.7% and 31.3% at 1, 2, and 3 years, respectively. CONCLUSIONS: Radiofrequency catheter ablation reduced implantable cardioverter-defibrillator shocks and VT episodes and improved quality of life at 6 months. A steady 3-year nonrecurrence rate with reduced amiodarone use and hospitalizations indicate improved long-term outcomes. (NaviStar ThermoCool Catheter for Endocardial RF Ablation in Patients With Ventricular Tachycardia [THERMOCOOL VT]; NCT00412607).

Prognosis of Myocardial Damage in Sarcoidosis Patients With Preserved Left Ventricular Ejection Fraction: Risk Stratification Using Cardiovascular Magnetic Resonance.

BACKGROUND: Cardiac sarcoidosis is associated with an increased risk of heart failure and sudden death, but its risk in patients with preserved left ventricular ejection fraction is unknown. Using cardiovascular magnetic resonance in patients with extracardiac sarcoidosis and preserved left ventricular ejection fraction, we sought to (1) determine the prevalence of cardiac sarcoidosis or associated myocardial damage, defined by the presence of late gadolinium enhancement (LGE), (2) quantify their risk of death/ventricular tachycardia (VT), and (3) identify imaging-based covariates that predict who is at greatest risk of death/VT. METHODS AND RESULTS: Parameters of left and right ventricular function and LGE burden were measured in 205 patients with left ventricular ejection fraction >50% and extracardiac sarcoidosis who underwent cardiovascular magnetic resonance for LGE evaluation. The association between covariates and death/VT in the entire group and within the LGE+ group was determined using Cox proportional hazard models and time-dependent receiver-operator curves analysis. Forty-one of 205 patients (20%) had LGE; 12 of 205 (6%) died or had VT during follow-up; of these, 10 (83%) were in the LGE+ group. In the LGE+ group (1) the rate of death/VT per year was >20× higher than LGE- (4.9 versus 0.2%, P<0.01); (2) death/VT were associated with a greater burden of LGE (14±11 versus 5±5%, P<0.01) and right ventricular dysfunction (right ventricular EF 45±12 versus 53±28%, P=0.04). LGE burden was the best predictor of death/VT (area under the receiver-operating characteristics curve, 0.80); for every 1% increase of LGE burden, the hazard of death/VT increased by 8%. CONCLUSIONS: Sarcoidosis patients with LGE are at significant risk for death/VT, even with preserved left ventricular ejection fraction. Increased LGE burden and right ventricular dysfunction can identify LGE+ patients at highest risk of death/VT.

Impact of baseline PR interval on cardiac resynchronization therapy outcomes in patients with narrow QRS complexes: an analysis of the ReThinQ Trial.

PURPOSE: Heart failure (HF) is a major cause of morbidity and mortality, and ventricular dyssynchrony is an important contributor. The ReThinQ trial reported no improvement with cardiac resynchronization therapy (CRT) in HF patients with left ventricular ejection fraction (LVEF) <35%, narrow QRS (<130 ms), New York Heart Association (NYHA) class III, and echocardiographically detected dyssynchrony, in spite of echocardiographic optimization. We investigated whether a subset of narrow QRS patients might derive benefit from CRT, based on baseline PR interval. METHODS: We retrospectivelyanalyzed the 87 patients from ReThinQ who were randomized to CRT. Patients were divided into two groups: baseline PR interval <180 ms and baseline PR interval ≥180 ms. The primary outcome was change in VO2 max at 6 months; secondary outcomes were change in LVEF, 6-min walk distance, and change in NYHA class. RESULTS: Forty-six patients had PR < 180 ms and 41 had PR ≥ 180 ms. The baseline characteristics were similar in the two groups. As compared to patients with a short PR interval, at 6 months, only patients with PR ≥ 180 ms showed a statistically significant increase in VO2 max from 12.2 to 13.6 mL/kg min (P = 0.045). Similarly, LVEF was significantly improved only in the long PR group (0.26 to 0.28, P = 0.038). A greater percentage of patients in the long PR group showed improvement by at least one NYHA class (59 vs. 35%, P = 0.033). CONCLUSIONS: A longer baseline PR interval may allow more efficacious delivery of CRT by allowing programming of physiologic AV delays. A short baseline PR interval may contribute to LV under-filling and CRT non-response.

Cardiac sarcoidosis detected by late gadolinium enhancement and prevalence of atrial arrhythmias.

Cardiovascular magnetic resonance (CMR) imaging is being increasingly used to help identify patients with cardiac sarcoidosis (CS). Whereas ventricular arrhythmias have been well studied in this population, atrial arrhythmias have not been thoroughly investigated. We sought to better characterize the arrhythmia burden of a cohort of patients diagnosed with CS by CMR imaging. Patients with biopsy-proven extracardiac sarcoidosis were referred to the University of Chicago for evaluation of the presence of CS. CMR imaging was used to categorize the patients into 2 groups; those with and those without late gadolinium enhancement (LGE) for comparison of arrhythmic events. Arrhythmic evaluation included Holter monitor, event recorder, electrophysiology testing, or implantable cardioverter-defibrillator (ICD) interrogation; 192 consecutive patients were evaluated with CMR imaging, 57 of whom did not have ambulatory monitoring results and thus were excluded. LGE was present in 44 patients. Atrial arrhythmias were documented in 16 patients (36%) with myocardial LGE and in 11 patients (12%) without myocardial LGE (p = 0.002). Ventricular arrhythmias were documented in 27% of patients with myocardial LGE and 2.2% of LGE-negative patients (p = 0.00076). Of 26 LGE-positive patients with ICDs, 8 (30.8%) received therapies, 3 (11.5%) of which were inappropriate for atrial arrhythmias. In conclusion, atrial arrhythmias were documented more frequently than ventricular arrhythmias in patients with sarcoidosis with cardiac involvement and were 3 times more prevalent than in patients with sarcoidosis without cardiac involvement. Risk-benefit assessment of anticoagulation for primary prevention of stroke should be performed for patients with CS. In patients receiving implantable defibrillators, programming to minimize inappropriate ICD shocks for atrial arrhythmias must be considered.

ICD lead parameters, performance, and adverse events following continuous-flow LVAD implantation.

BACKGROUND: Ventricular arrhythmias (VAs) in the months following continuous-flow left ventricular assist devices (LVADs) implantation are common and associated with increased morbidity and mortality. We sought to evaluate for changes in implantable cardioverter defibrillator (ICD) performance following LVAD implantation. METHODS: We retrospectively reviewed the ICD interrogation reports and medical records of patients who received a continuous-flow LVAD at the University of Chicago Medical Center between January 2008 and December 2010. Patients who did not have an ICD prior to LVAD implantation were excluded. RESULTS: Forty-four patients were included. Median right ventricular lead sensing amplitude decreased from 10.0 (interquartile range 7.6-13.6) mV prior to LVAD to 7.9 (5.9-9.3) mV after LVAD implantation (P < 0.01). Significant reductions in sensing threshold were associated with smaller lead diameters, smaller pace/sense electrode surface areas, and Medtronic ICD leads (Medtronic Inc., Minneapolis, MN, USA). Lead impedance and capture threshold did not change significantly. ICD-related adverse events occurred in 30% of patients and led to ICD modification in 18% of patients. CONCLUSIONS: Implantation of a continuous-flow LVAD is associated with changes in the performance of preexisting ICDs. ICD-related adverse events were encountered following LVAD implantation in this cohort, and at times resulted in invasive and noninvasive ICD system modification. Reductions in ICD sensing threshold after LVAD implantation may adversely affect ICD function. Formal ICD interrogation in addition to the regular follow-up testing is warranted post-LVAD.

Effect of defibrillation threshold testing-induced ventricular fibrillation on renal function.

INTRODUCTION: The effect of defibrillation threshold (DFT) testing with induction of ventricular fibrillation (VF) on renal function is currently unknown. This study examined the acute effect of DFT testing on renal function in patients undergoing implantable cardioverter defibrillator (ICD) implantation. METHODS AND RESULTS: We performed a prospective cohort study of 148 consecutive patients who underwent ICD implantation from January 1, 2007 to May 30, 2008. Patients were assigned to one of two cohorts: a DFT group who underwent DFT testing at device implantation and a no-DFT group that was not tested. Baseline and 24-h postprocedure renal function were assessed with measurements of serum creatinine and estimated glomerular filtration rate (GFR) by the Modified Diet in Renal Disease equation. Changes in serum creatinine and estimated GFR were compared between cohorts. Ninety-eight patients (66%) underwent DFT testing (average VF induction count, 1.5 ± 0.9; mean VF duration, 10 ± 4 s). Fifty patients (34%) were not tested. Patients in the no-DFT group had lower mean left ventricular ejection fraction, higher New York Heart Association class, higher atrial fibrillation incidence, and greater intravenous contrast utilization at device implant. Baseline and postprocedure serum creatinine values were similar between groups (baseline, 1.25 ± 0.45 mg/dL; post-ICD, 1.26 ± 0.5 mg/dL). Baseline GFR was lower in the DFT cohort (55.2 ± 18.8 mL/min/BSA vs 63.7 ± 22.7 mL/min/BSA, p = 0.023). No significant differences between groups were observed in the mean change in serum creatinine or estimated GFR. CONCLUSIONS: DFT testing at the time of ICD implantation is not associated with acute adverse effects on renal function.

Elevated S100A12 and sRAGE are associated with increased length of hospitalization after non-urgent coronary artery bypass grafting surgery.

UNLABELLED: Study's purpose: Plasma levels of soluble receptor for advanced glycation endproducts (sRAGE) and S100A12 are increased in young children after cardiac surgery and correlate with the time spent on cardiopulmonary bypass (CPB). This study was performed to investigate whether plasma levels of sRAGE and S100A12 are affected by the use of CPB. Levels of S100A12 and sRAGE, along with of interleukin-6, tumor necrosis factor-α, myeloperoxidase, and C-reactive protein were measured in 25 adults undergoing non-urgent coronary artery bypass grafting with and without the use of CPB. Significant finding: Plasma levels of S100A12, sRAGE, IL-6, TNF-α and MPO 4h after cardiac surgery were elevated compared to baseline; this increase was equally observed in patients undergoing traditional coronary artery bypass grafting on cardiopulmonary bypass (n = 16), and in patients undergoing robot-assisted coronary artery bypass grafting off pump (OPCAB, n = 9). Patients with prolonged hospitalization of 7 days or longer had significantly higher S100A12 and sRAGE 4 hours post surgery compared to patients hospitalized ≤ 6 days. CONCLUSION: Increased sRAGE and S100A12 after cardiac surgery is associated with prolonged length of hospitalization in patients after coronary artery bypass grafting; however, we did not observe an intrinsic effect of cardiopulmonary bypass on S100A12 or sRAGE plasma levels in our small pilot study. Further studies are required to confirm the value of sRAGE and S100A12 in predicting postoperative complications after cardiac surgery in a larger study.

Ranolazine safely decreases ventricular and atrial fibrillation in Timothy syndrome (LQT8).

Long QT eight (LQT8), otherwise known as Timothy syndrome (TS), is a genetic disorder causing hyper-activation of the L-type calcium channel Cav 1.2. This calcium load and the resultant increase in the QT interval provide the substrate for ventricular arrhythmias. We previously presented a case in a patient with TS who had a profound decrease in his burden of ventricular arrhythmias after institution of an L-type calcium channel blocker. Although this patient's arrhythmia burden had decreased, he displayed an increasing burden of atrial fibrillation and still had bouts of ventricular fibrillation requiring defibrillator therapy. Basic research has recently shown that ranolazine, a multipotent ion-channel blocker, may be of benefit in patients with LQT8 syndrome. This case report details the decrease of atrial fibrillation and ventricular fibrillation events in our LQT8 patient with the addition of ranolazine.