Monther Boulos

Modelling the long QT syndrome with induced pluripotent stem cells

The ability to generate patient-specific human induced pluripotent stem cells (iPSCs) offers a new paradigm for modelling human disease and for individualizing drug testing. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current IKr. Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, KATP-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies.

Fasting glucose is an important independent risk factor for 30-day mortality in patients with acute myocardial infarction: a prospective study.

Background—Stress hyperglycemia in patients with acute myocardial infarction has been associated with increased mortality. Most studies looked at the relationship between admission glucose (AG) and outcome; limited information is available about the clinical significance of fasting glucose (FG). Methods and Results—We prospectively studied the relationship between FG and 30-day mortality in 735 nondiabetic patients with acute myocardial infarction. FG (≥8-hour fast within 24 hours of admission) and AG were measured in each patient. At 30 days, 9 deaths (2%) occurred in patients with normal FG, and 11 (10%), 14 (13%), and 31 (29%) deaths occurred in the first, second, and third tertiles of elevated FG, respectively. Compared with normal FG (<110 mg/dL), the adjusted OR for 30-day mortality progressively increased with higher tertiles of elevated FG (first tertile, 4.6; 95% CI, 1.7 to 12.7; P=0.003; second tertile, 6.4; 95% CI, 2.5 to 16.6; P<0.0001; third tertile, 11.5; 95% CI, 4.7 to 20.0; P<0.0001). Compared with patients categorized as having normal AG (<140 mg/d), the adjusted ORs for tertiles of elevated AG were as follows: first tertile, 1.4 (95% CI, 0.5 to 3.8; P=0.54); second tertile, 3.0 (95% CI, 1.3 to 7.0; P=0.01); and third tertile, 4.4 (95% CI, 2.0 to 9.7; P<0.0001). Compared with patients with normal FG and AG, the adjusted ORs for 30-day mortality were 0.71 (95% CI, 0.15 to 3.4; P=0.67) in patients with elevated AG and normal FG, 3.4 (95% CI, 1.1 to 10.4; P=0.03) for patients with normal AG glucose and elevated FG, and 9.6 (95% CI, 3.5 to 26.0; P<0.0001) for patients with both elevated FG and AG. Comparing nested models showed that including AG failed to improve the prediction of the model based on FG (&khgr;2=5.4, 3 df, P=0.15). In contrast, the addition of FG classes to the model based on AG improved model prediction (&khgr;2=22.4, 3 df, P<0.0001). Conclusions—There is a graded relation between elevated FG and AG and 30-day mortality in patients with acute myocardial infarction. FG is superior to AG in the assessment of short-term risk. (Circulation. 2005;111:754-760.)

Circadian pattern of life-threatening ventricular arrhythmia in patients with sleep-disordered breathing and implantable cardioverter-defibrillators

BACKGROUND Sleep-disordered breathing (SDB) has been associated with various benign cardiac arrhythmias occurring during sleep. OBJECTIVE The purpose of this study was to demonstrate that SDB contributes to the development of life-threatening ventricular arrhythmias in patients with an established arrhythmic substrate. METHODS We prospectively studied the association between SDB and timing of life-threatening ventricular arrhythmic events in 45 patients with an implantable cardioverter-defibrillator (ICD). SDB was defined as an apnea-hypopnea index (AHI) >10 events/hour based on an overnight sleep study. The primary outcome measure was appropriate ICD therapy, defined as antitachycardia pacing or shock for ventricular tachycardia or ventricular fibrillation during 1-year follow-up. RESULTS SDB was present in 26 (57.8%) patients. Appropriate ICD therapies were higher among patients with SDB (73% vs 47%, P = .02). Logistic regression identified SDB as a predictor of any appropriate ICD therapy (odds ratio 4.4, 95% confidence interval 1.4-15.3, P = .01). The risk for ventricular arrhythmias was higher in patients with SDB solely due to an increase in events occurring between midnight and 6 AM (odds ratio 5.6, 95% confidence interval 2.0-15.6, P = .001) with no discernible effect on appropriate ICD therapy during nonsleeping hours (odds ratio 0.7, 95% confidence interval 0.2-2.3, P = .61). CONCLUSION Patients with an ICD and SDB have a striking increase in the onset of life-threatening ventricular arrhythmic events during sleeping hours. These findings provide a rationale for SDB screening in patients with appropriate ICD therapy if device interrogation reveals a predominance of nocturnal onset of arrhythmias.

Stent deployment failure: reasons, implications, and short- and long-term outcomes.

Stents have revolutionized percutaneous coronary interventions (PCI), impacting on both acute and long‐term results. However, despite improvements in stent design, stent deployment failure is not an unusual event. The aim of the present study was to assess the frequency and causes of stent deployment failure, as well as the outcome of these patients. Between 1997 and 2001, a total of 3,537 patients underwent stent‐assisted PCI and delivery of 5,275 stents was attempted. In the majority of patients (118; 78.1%), stenting was performed as provisional; in the remaining 33 (21.8%) as a bailout procedure. A total of 175 (3.3%) stents in 151 (4.3%) patients failed. Failure to deliver the stent to the lesion site was the main cause in 139 patients (92%) and failure either to expand adequately the stent or premature disengagement of the stent from the balloon in only 12 patients (8%). Peripheral stent embolization occurred in 10 (0.3%) patients. Deployment of a different stent in place of the failed one was attempted in 122 patients and was successful in the majority (108; 88.5%). In‐hospital major adverse cardiac events were observed in six patients (4%): three patients required emergency coronary artery bypass surgery, two had a myocardial infarction (MI), and one patient underwent urgent repeat coronary intervention. At a mean follow‐up of 32.2 ± 17.7 months, 22 major adverse cardiac event occurred in 17 patients (11.2%): 1 cardiac death, 3 patients had an MI, and 18 patients required target vessel revascularization. One‐year event‐free survival for the whole group was 91.2%. Patients with stent embolization did not have any major adverse cardiac or vascular events. Thus, the rate of stent deployment failure in our series was 3.3%, mainly due to failure to deliver the stent to the site. Another stent was successfully deployed in the majority of cases and these patients had favorable short‐ and long‐term outcomes. Cathet Cardiovasc Intervent 2003;59:324–328.

Stenting very small coronary narrowings (< 2 mm) using the biocompatible phosphorylcholine‐coated coronary stent

Published data regarding stenting very small arteries are still limited. The BiodivYsio stent is a new stent coated with phosphorylcholine, a biocompatible molecule designed to reduce the formation of thrombus and potentially the risk of restenosis. The feasibility, safety, and efficacy of implantation of the 2.0 mm coated coronary stent were prospectively studied. We studied 97 patients from three centers who underwent elective, urgent, or bailout implantation of 106 BiodivYsio mini‐stents (2.0 mm) in 101 lesions. Forty percent of lesions had unfavorable characteristics (type B2 or C) and 16% had thrombus and/or chronic total occlusion. Successful stent deployment was achieved in 100/101 lesions (99%). MLD increased from 0.49 ± 0.31 mm to 1.89 ± 0.41 mm and diameter stenosis decreased from 89% ± 7% to 5.6% ± 6%. Small vessel stenting was the only procedure in 71% patients. There was one acute stent thrombosis case. During 6‐month follow‐up, none died, one had MI, and one was referred to CABG due to nontarget lesion progression. Angiographic restenosis that required target lesion revascularization was performed in 8/18 that had catheterization due to chest pain or significant ischemia. Most patients improved in their clinical symptoms. The rate of major adverse cardiac events was 4.1% at 30‐day and 10.3% at 6‐month follow‐up. This initial clinical experience indicates that the implantation of 2.0 mm stents coated with phosphorylcholine appears to be safe and efficacious in the treatment of complex coronary lesions and is associated with low target vessel revascularization rate in spite of the very small vessel diameter. Cathet Cardiovasc Intervent 2002;55:303–308.

Age Dependence of Complete Heart Block Complicating Radiofrequency Ablation of the Atrioventricular Nodal Slow Pathway

A significant age dependence of the risk of complete heart block complicating radiofrequency ablation of the AV nodal slow pathway was noticed, with no patients <45 years of age experiencing this complication.

Patient safety and outcomes from live case demonstrations of interventional cardiology procedures

OBJECTIVES The goal of this study was to examine the safety and results of interventional procedures performed during the broadcast of live case demonstrations. BACKGROUND Professional meetings using live case demonstrations to present cutting-edge technology are considered a valuable educational resource. There is an ongoing discussion on whether patients who are treated during live case demonstrations are exposed to a higher risk. METHODS Between 1998 and 2010, 101 patients were treated during live transmissions from a single center in 15 invasive-cardiology conferences. Technical success was defined as the ability to effectively perform the planned procedure without any major complication. The primary endpoint of the study was the composite occurrence of death, myocardial infarction, or stroke. RESULTS The interventional procedures included coronary (n=66), carotid (n=15), peripheral (n=1), valvular (n=2), congenital heart disease (n=12), and complex electrophysiological mapping and ablation interventions (n=7). In 4 cases, the intended procedure was not done. The procedure was technically successful in 95%. In 5 cases, the procedure was unsuccessful because of the inability to cross a chronic total occlusion. There were no deaths during the hospital stay, and the composite primary endpoint occurred in 2 patients: a minor stroke following an atrial fibrillation ablation and a rise in serum troponin levels after percutaneous coronary intervention. These results were no different from those of 66 matched controls who underwent procedures performed by the same operators but not as live case demonstrations (relative risk: 0.32; 95% confidence interval: 0.02 to 3.62, p=0.62). CONCLUSIONS In this consecutive series of interventional cardiology procedures that were performed by expert operators during live demonstration courses, the procedural and 30-day clinical outcomes were similar to those found in daily practice and to those that have been reported in the contemporary published data. These results suggest that broadcasting live case demonstrations in selected patients from selected centers may be safe.

Importance of ventricular tachycardia storms not terminated by implantable cardioverter defibrillators shocks in patients with CASQ2 associated catecholaminergic polymorphic ventricular tachycardia.

In this study, the clinical and implantable cardioverter-defibrillator (ICD)-related follow-up of patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) with homogenous missense mutations in CASQ2 was summarized. Patients were followed in a pediatric cardiology clinic and an ICD clinic. All patients were treated with high-dose β blockers. ICDs were recommended for patients who remained symptomatic despite medical treatment. Twenty-seven patients were followed for 1 to 15 years (median 9). Twenty patients (74%) were symptomatic at diagnosis; 13 (65%) remained symptomatic after treatment with high-dose β blockers and thus were advised to receive ICDs. Eight of these patients refused ICDs, and eventually 6 (75%) died suddenly. Four of the 5 patients who received ICDs had ventricular tachycardia storms treated but not terminated by recurrent ICD shocks. These ventricular tachycardia storms (2 episodes in 2 patients and 1 episode in 2 patient) terminated spontaneously after finishing the programmed ICD shocks, without degeneration to ventricular fibrillation. None of the patients who received ICDs died. In conclusion, patients with CASQ2-associated CPVT should be recommended to receive ICDs to prevent sudden death when medical therapy is not effective. These patients may have recurrent ventricular tachycardia storms treated but not terminated by recurrent ICD shocks, without degeneration to ventricular fibrillation.

Power Spectral Analysis of Heart Rate Variability during Upright Tilt Test: A Comparison of Patients with Syncope and Normal Subjects

We analyzed heart variability (HRV) response to tilt in 35 patients with a history of neurocardiogenic syncope and in 8 normal volunteers. Frequency domain examination was performed using power spectral analysis of RR variability during resting supine position and during the 256 beats preceding the onset of syncope or completion of 60 min of upright tilt to 70 degrees. Both low (0.05-0.15 Hz) and high frequency (0.15-0.4 Hz) spectral components of HRV increased markedly in all groups as a result of tilting. Statistically significant differences were noted between the patient groups at completion of upright tilting. However, these differences in spectral components between groups were of small magnitude when compared to the overall increase in spectral power occurring in all groups as a result of the tilt and are difficult to correlate clinically with the appearance, or lack of appearance of tilt-induced syncope. Power spectral analysis of HRV, as presently performed, appears to lack discriminative power to detect the rapid and marked changes in sympathovagal modulation known to occur during tilt test in patients with neurocardiogenic syncope.

Clinical characteristics and outcomes of elderly patients treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy in a real-world setting: data from the Israeli ICD Registry.

BACKGROUND Elderly patients are underrepresented in clinical trials of device therapy. OBJECTIVE To provide real-world data regarding outcomes associated with device-based therapy in a large cohort of elderly patients enrolled in the Israeli ICD Registry. METHODS Between July 2010 and June 2012, a total of 2807 consecutive patients undergoing implanted cardioverter-defibrillator/cardiac resynchronization therapy-defibrillator (ICD/CRT-D) implantation were prospectively enrolled in the Israeli ICD Registry. For the present analysis, patients were categorized into 3 age groups: ≤60 years (n = 1378 [49%]), 61-75 years (n = 863 [31%]), and >75 years (n = 566 [20%]). RESULTS Elderly patients (>75 years of age) had more comorbid conditions and were more likely to undergo CRT-D implantation (all P < .01). However, the rate of device-related complications associated with surgical reinterventions at 1 year was <3% regardless of age (P = .70 for the comparison among the 3 age groups). Multivariate analysis showed that the risk of heart failure or death and of appropriate ICD therapy for ventricular arrhythmias was significantly increased with increasing age among patients who received an ICD. In contrast, the age-related increase in the risk of all end points was attenuated among patients who received CRT-D devices (all P values for age-by-device-type interactions are <.05). CONCLUSIONS In a real-world scenario, elderly patients (>75 years of age) comprise approximately 20% of the ICD/CRT-D recipients and experience a device reintervention rate similar to that of their younger counterparts. Our data suggest that the association between advanced age and adverse clinical outcomes is attenuated in elderly patients implanted with CRT-D devices.