Karim Sallam, MD

View details for DOI 10.1016/j.jelectrocard.2013.06.022

View details for PubMedID 23981305

Abstract

Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations.We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.

View details for DOI 10.1161/CIRCULATIONAHA.113.001883

View details for PubMedID 23519760

Abstract

Though early repolarization (ER) in the inferior leads has been associated with increased cardiovascular risk, its natural history is uncertain. We aimed to study the serial electrocardiographic behavior of inferior ER and understand factors associated with that behavior.We selected electrocardiograms (ECGs) from patients with the greatest amplitude of ER in AVF from ECGs of 29,281 ambulatory patients recorded between 1987 and 1999 at the Palo Alto Veterans Affairs Hospital. Starting from the highest amplitude, we reviewed the ECGs and medical records from the first 85%. From this convenience sample, 36 were excluded for abnormal patterns similar to ER. The remaining 257 patients were searched for another ECG at least 5 months later, of whom, 136 satisfied this criteria. These ECGs were paired for comparison and coded by four interpreters.The average time between the first and second ECGs was 10 years. Of the 136 subjects, 47% retained ER while 53% no longer fulfilled the amplitude criteria. While no significant differences were found in initial heart rate (HR) or time interval between ECGs, those who lost the ER pattern had a greater difference in HR between the ECGs. There was no significant difference in the incidence of cardiovascular events or deaths.In conclusion, the ECG pattern of ER was lost over 10 years in over half of the cohort. The loss of ER was partially explained by changes in HR, but not higher incidence of cardiovascular events or death, suggesting the entity is a benign finding.

View details for DOI 10.1111/j.1542-474X.2012.00537.x

View details for Web of Science ID 000310248100005

View details for PubMedID 23094879

Abstract

To evaluate the prevalence of early polarization (ER) in a stable population and to evaluate the prognostic significance of the association or absence of Q waves or T-wave inversion (TWI).In this retrospective study performed at the university-affiliated Palo Alto Veterans Affairs Health Care Center from March 1, 1987, through December 31, 1999, we evaluated outpatient electrocardiograms. Vital status and cause of death were determined in all patients, with a mean ± SD follow-up of 7.6±3.8 years.Of the 29,281 patients, 87% were men and 13% were African American. Inferior or lateral ER was present in 664 patients (2.3%): in inferior leads in 185 (0.6%), in lateral leads in 479 (1.6%) , and in both inferior and lateral leads in 163 (0.6%). Only when Q waves or TWI accompanied ER was there an increased risk of cardiovascular death (Cox proportional hazards regression model, 5.0; 95% confidence interval, 3.4-7.2; P<.001).Common patterns of ER without concomitant Q waves or TWI are not associated with increased risk of cardiovascular death; however, when either occurs with ER, there is a hazard ratio of 5.0. These findings confirm that ER is a benign entity; however, the presence of Q waves or TWI with ER is predictive of increased cardiovascular death.

View details for DOI 10.1016/j.mayocp.2012.04.009

View details for Web of Science ID 000306872800003

View details for PubMedID 22766081

Abstract

Embryonic stem (ES) cells have therapeutic potential in disorders of cellular loss such as myocardial infarction, type I diabetes and neurodegenerative disorders. ES cell biology in living subjects was largely poorly understood until incorporation of molecular imaging into the field. Reporter gene imaging works by integrating a reporter gene into ES cells and using a reporter probe to induce a signal detectable by normal imaging modalities. Reporter gene imaging allows for longitudinal tracking of ES cells within the same host for a prolonged period of time. This has advantages over postmortem immunohistochemistry and traditional imaging modalities. The advantages include expression of reporter gene is limited to viable cells, expression is conserved between generations of dividing cells, and expression can be linked to a specific population of cells. These advantages were especially useful in studying a dynamic cell population such as ES cells and proved useful in elucidating the biology of ES cells. Reporter gene imaging identified poor integration of differentiated ES cells transplanted into host tissue as well as delayed donor cell death as reasons for poor long-term survival in vivo. This imaging technology also confirmed that ES cells indeed have immunogenic properties that factor into cell survival and differentiation. Finally, reporter gene imaging improved our understanding of the neoplastic risk of undifferentiated ES cells in forming teratomas. Despite such advances, much remains to be understood about ES cell biology to translate this technology to the bedside, and reporter gene imaging will certainly play a key role in formulating this understanding.

View details for DOI 10.1007/978-1-60761-705-1_12

View details for PubMedID 20680820