Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue.

Jervell and Lange-Nielsen syndrome (JLNS) is one of the most severe life-threatening cardiac arrhythmias. Patients display delayed cardiac repolarization, associated high risk of sudden death due to ventricular tachycardia, and congenital bilateral deafness. In contrast to the autosomal dominant forms of long QT syndrome, JLNS is a recessive trait, resulting from homozygous (or compound heterozygous) mutations in KCNQ1 or KCNE1. These genes encode the α and ß subunits, respectively, of the ion channel conducting the slow component of the delayed rectifier K(+) current, IKs. We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1. Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs. We show that this phenotype had distinct underlying molecular mechanisms in the two sets of cell lines: the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane. Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS-CMs. Furthermore, sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs but could be pharmacologically corrected. Our data provide mechanistic insight into distinct classes of JLNS-causing mutations and demonstrate the potential of hiPSC-CMs in drug evaluation.

Serum supplemented culture medium masks hypertrophic phenotypes in human pluripotent stem cell derived cardiomyocytes.

It has been known for over 20 years that foetal calf serum can induce hypertrophy in cultured cardiomyocytes but this is rarely considered when examining cardiomyocytes derived from pluripotent stem cells (PSC). Here, we determined how serum affected cardiomyocytes from human embryonic- (hESC) and induced pluripotent stem cells (hiPSC) and hiPSC from patients with hypertrophic cardiomyopathy linked to a mutation in the MYBPC3 gene. We first confirmed previously published hypertrophic effects of serum on cultured neonatal rat cardiomyocytes demonstrated as increased cell surface area and beating frequency. We then found that serum increased the cell surface area of hESC- and hiPSC-derived cardiomyocytes and their spontaneous contraction rate. Phenylephrine, which normally induces cardiac hypertrophy, had no additional effects under serum conditions. Likewise, hiPSC-derived cardiomyocytes from three MYBPC3 patients which had a greater surface area than controls in the absence of serum as predicted by their genotype, did not show this difference in the presence of serum. Serum can thus alter the phenotype of human PSC derived cardiomyocytes under otherwise defined conditions such that the effects of hypertrophic drugs and gene mutations are underestimated. It is therefore pertinent to examine cardiac phenotypes in culture media without or in low concentrations of serum.

Remote monitoring of patients with implanted devices: data exchange and integration.

BACKGROUND: Remote follow-up of implanted implantable cardioverter defibrillators (ICDs) may offer a solution to the problem of overcrowded outpatient clinics, and may also be effective in detecting clinical events early. Data obtained from remote follow up systems, as developed by all major device companies, are stored in a central database system, operated and owned by the device company. A problem now arises that the patient's clinical information is partly stored in the local electronic health record (EHR) system in the hospital, and partly in the remote monitoring database, which may potentially result in patient safety issues. METHODS: To address the requirement of integrating remote monitoring data in the local EHR, the Integrating the Healthcare Enterprise (IHE) Implantable Device Cardiac Observation (IDCO) profile has been developed. This IHE IDCO profile has been adapted by all major device companies. RESULTS: In our hospital, we have implemented the IHE IDCO profile to import data from the remote databases from two device vendors into the departmental Cardiology Information System (EPD-Vision). Data is exchanged via a HL7/XML communication protocol, as defined in the IHE IDCO profile. CONCLUSIONS: By implementing the IHE IDCO profile, we have been able to integrate the data from the remote monitoring databases in our local EHRs. It can be expected that remote monitoring systems will develop into dedicated monitoring and therapy platforms. Data retrieved from these systems should form an integral part of the electronic patient record as more and more out-patient clinic care will shift to personalized care provided at a distance, in other words at the patient's home.

Acute Myocardial Infarction with Hyperoxemic Therapy (AMIHOT): a prospective, randomized trial of intracoronary hyperoxemic reperfusion after percutaneous coronary intervention.

OBJECTIVES: This study sought to determine whether hyperoxemic reperfusion with aqueous oxygen (AO) improves recovery of ventricular function after percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND: Hyperbaric oxygen reduces myocardial injury and improves ventricular function when administered during ischemia-reperfusion. METHODS: In a prospective, multicenter study, 269 patients with acute anterior or large inferior AMI undergoing primary or rescue PCI (<24 h from symptom onset) were randomly assigned after successful PCI to receive hyperoxemic reperfusion (treatment group) or normoxemic blood autoreperfusion (control group). Hyperoxemic reperfusion was performed for 90 min using intracoronary AO. The primary end points were final infarct size at 14 days, ST-segment resolution, and delta regional wall motion score index of the infarct zone at 3 months. RESULTS: At 30 days, the incidence of major adverse cardiac events was similar between the control and AO groups (5.2% vs. 6.7%, p = 0.62). There was no significant difference in the incidence of the primary end points between the study groups. In post-hoc analysis, anterior AMI patients reperfused <6 h who were treated with AO had a greater improvement in regional wall motion (delta wall motion score index = 0.54 in control group vs. 0.75 in AO group, p = 0.03), smaller infarct size (23% of left ventricle in control group vs. 9% of left ventricle in AO group, p = 0.04), and improved ST-segment resolution compared with normoxemic controls. CONCLUSIONS: Intracoronary hyperoxemic reperfusion was safe and well tolerated after PCI for AMI, but did not improve regional wall motion, ST-segment resolution, or final infarct size. A possible treatment effect was observed in anterior AMI patients reperfused <6 h of symptom onset.

Electrophysiological and arrhythmogenic effects of intramyocardial bone marrow cell injection in patients with chronic ischemic heart disease.

BACKGROUND: Bone marrow cell injection has been introduced to treat patients with ischemic heart disease. However, focal application of bone marrow cells may generate an arrhythmogenic substrate. OBJECTIVES: To assess the electrophysiological and arrhythmogenic effects of intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia. METHODS: Bone marrow was aspirated in 20 patients (65+/-11 years, 19 male) with drug-refractory angina and myocardial ischemia. Electroanatomical mapping (NOGA, Biosense-Webster, Waterloo, Belgium) was performed during mononuclear cell isolation. Areas for cell injection were selected based on the localization of ischemia on SPECT. These areas were mapped in detail to evaluate local bipolar electrogram duration, amplitude and fragmentation. Mononuclear cells were injected in the ischemic area with the NOGA system. SPECT and electroanatomical mapping were repeated at 3 months. Holter monitoring was repeated at 3 and 6 months. RESULTS: SPECT revealed a decrease in the number of segments with ischemia (3.5+/-2.5 vs. 1.1+/-1.0 at 3 months; P<0.01) and an increased left ventricular ejection fraction (44+/-13% vs. 49+/-17% at 3 months; P=0.02). The number of ventricular premature beats remained unchanged (10+/-24x10(2)/24h vs. 8+/-23x10(2)/24h at 3 months (P=NS) and 12+/-30x10(2)/24h at 6 months (P=NS)). At 3 months follow-up, bone marrow cell injection did not prolong electrogram duration (15.9+/-4.6 ms vs. 15.6+/-4.0 ms; P=NS), decrease electrogram amplitude (3.8+/-1.5 mV vs. 3.8+/-1.5 mV; P=NS), or increase fragmentation (2.0+/-0.5 vs. 1.9+/-0.4; P=NS). CONCLUSION: Intramyocardial bone marrow cell injection does not increase the incidence of ventricular arrhythmias and does not alter the electrophysiological properties of the injected myocardium.

A comparative regional analysis of coronary atherosclerosis and calcium score on multislice CT versus myocardial perfusion on SPECT.

UNLABELLED: For the noninvasive evaluation of coronary artery disease (CAD), both multislice CT and gated SPECT are available. How these 2 modalities relate, however, is yet unclear. The purpose of this study was to perform a head-to-head comparison of the results of multislice CT and gated SPECT on a regional basis (per vessel distribution territory) in patients with known or suspected CAD. METHODS: One hundred forty patients underwent both multislice CT for coronary calcium scoring and coronary angiography and gated SPECT for myocardial perfusion imaging. The coronary calcium score was determined for each coronary artery. Coronary arteries on multislice CT angiography were classified as having no CAD, insignificant stenosis (<50% luminal narrowing), significant stenosis, or total or subtotal occlusion (>/=90% luminal narrowing). Gated SPECT findings were classified as normal or abnormal (reversible or fixed defects) and were allocated to the territory of one of the various coronary arteries. RESULTS: In coronary arteries with a calcium score of 10 or less, the corresponding myocardial perfusion was normal in 87% (n = 194/224). In coronary arteries with extensive calcifications (score > 400), the percentage of vascular territories with normal myocardial perfusion was lower, 54% (n = 13/24). Similarly, in most of the normal coronary arteries on multislice CT angiography, the corresponding myocardial perfusion was normal on SPECT (156/175, or 89%). In contrast, the percentage of normal SPECT findings was significantly lower in coronary arteries with obstructive lesions (59%) or with total or subtotal occlusions (8%) (P < 0.01). Nonetheless, only 48% of vascular territories with normal perfusion corresponded to normal coronary arteries on multislice CT angiography, whereas insignificant and significant stenoses were present in, respectively, 40% and 12% of corresponding coronary arteries. CONCLUSION: Although a relationship exists between the severity of CAD on multislice CT and myocardial perfusion abnormalities on SPECT, analysis on a regional basis showed only moderate agreement between observed atherosclerosis and abnormal perfusion. Accordingly, multislice CT and gated SPECT provide complementary rather than overlapping information, and further studies should address how these 2 modalities can be integrated to optimize patient management.

Effect of intracoronary aqueous oxygen on left ventricular remodeling after anterior wall ST-elevation acute myocardial infarction.

The present report describes outcomes of randomized selective intracoronary aqueous oxygen versus standard care in patients who had acute anterior wall myocardial infarction within 6 hours of onset (n = 50). Left ventricular (LV) dimensions and function were assessed by contrast echocardiography at baseline and 1 month. It is demonstrated that aqueous oxygen prevents LV remodeling and preserves LV ejection fraction.