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Abstract 115: Nuclear CaMKII is a Histone H3 Kinase that Remodels Chromatin During Cardiac Hypertrophy
- Salma Mahmoud,
- Muhammad Kunhi,
- Gillian H Little,
- Yan Bai,
- Woojin An,
- Larry Kedes and
- Coralie Poizat
Circulation Research Volume 113, Issue suppl_11 August 2013

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Background and Purpose: Calcium/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous serine/threonine kinase implicated in pathological events such as cardiac hypertrophy. In this study we investigated the role of a specific nuclear isoform of CaMKII in chromatin remodeling and in transcriptional regulation in cardiac muscle.Methods: Comprehensive experimental approaches performed in primary cardiomyocyte cultures were used including chromatin immunoprecipitation assays (ChIP), q-PCR, chromatin remodeling assays, in vitro phosphorylation/transcription assays, production of recombinant adenovirus, siRNA technology, fluorescence microscopy and mass spectrometry.Results: We found that CaMKIIδB targets specific components of chromatin during cardiac hypertrophy and binds to nucleosomes through its association domain in a cooperative model. CaMKIIδB also increased chromatin relaxation, and this action was dependent on its kinase activity. The observation that CaMKIIδB interacts with chromatin suggested to us that histones maybe novel substrates of the kinase in cardiac muscle. To test this hypothesis, we performed in vitro kinase assays and found that histone H3 is a bona fide CaMKIIδB substrate and Ser-10 appears to be a predominant phosphorylation site. Increased histone H3 Ser-10 phosphorylation was observed following hypertrophic stimulation and was not associated with cellular proliferation, whereas depletion of CaMKIIδB significantly reduced histone H3 Ser-10 phosphorylation in primary cardiomyocytes. Interestingly, we found that H3 S10 phosphorylation and recruitment of CaMKIIδB occur at promoters of fetal cardiac genes. To establish the functional link between H3 phosphorylation by CaMKIIδB, chromatin remodeling and transcription activation, we developed an in vitro transcription system and using it we found that CaMKIIδB increased chromatin accessibility and mediated transcription of the Mef2 transcription factor.Conclusion: Taken together, these findings highlight a new role of CaMKIIδB as relevant histone H3 kinase and link for the first time epigenetic changes by CaMKII to cardiac hypertrophy.
Fasting Glucose Is an Important Independent Risk Factor for 30-Day Mortality in Patients With Acute Myocardial Infarction: A Prospective Study
- Mahmoud Suleiman,
- Haim Hammerman,
- Monther Boulos,
- Michael R. Kapeliovich,
- Abeer Suleiman,
- Yoram Agmon,
- Walter Markiewicz and
- Doron Aronson
Circulation Volume 111, Issue 615 February 2005

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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 (χ²=5.4, 3 df, P=0.15). In contrast, the addition of FG classes to the model based on AG improved model prediction (χ²=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.
Abstract TP409: Cognitive Function in Cerebral Arteriopathy: An Evaluation of the Effects of Blood Pressure and Body Mass Index
- Mahmoud Slim,
- Stephanie Dephoure,
- Robyn Westmacott,
- Chloe Chow,
- Mahendranath Moharir,
- Elizabeth Pulcine,
- Daune MacGregor,
- Edgar Jaeggi and
- Nomazulu Dlamini
Stroke Volume 51, Issue Suppl_1

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Background: Cerebral arteriopathy (CA) is a major risk factor for childhood arterial ischemic stroke and is associated with significant cognitive impairments. Disease-related characteristics partially explain the variability observed in specific cognitive outcomes. Adult studies demonstrate an association between stroke risk factors such as increased body mass index (BMI) and blood pressure (BP) and cognitive function, suggesting a more diffuse mechanism of brain injury. We aimed to evaluate the association between BMI and BP with cognitive function in children with CA.Methods: We conducted a cross-sectional study in children with CA and no stroke, aged 5-18 years. Children were evaluated using Wechsler Intelligence Scale for Children (WISC), Adaptive Behaviour Assessment System (ABAS), Beery-Buktenica Developmental Test (BEERY) and Behaviour Assessment System for Children (BASC). Children with BMI≥85^th percentile were classified as overweight and those with systolic or diastolic BP≥90^th percentile were classified as prehypertensive/hypertensive (Pre-HTN).Results: Of 88 children with CA, 38 were included (63% female; median age:11.3 years). Pre-HTN and overweight were present in 26% and 29%, respectively. Significant negative correlations were found between BMI and working memory (R²=-0.5, p=0.01) and perceptual reasoning (R²=-0.4, p=0.04) of the WISC. Beery-perception scores correlated significantly with diastolic BP (R²=-0.5, p=0.02) and BMI (R²=-0.7, p=0.01). The social composite score of the ABAS correlated significantly with the BMI (R²=-0.7, p=0.04). Overweight children had significantly lower BEERY-motor scores (53.5±30.4 vs 84.8±17.8, p=0.03) and higher BASC-externalizing problems (58±11.4 vs 47.9±8.4, p=0.02) compared to children with normal weight. Hypertensive children displayed significantly lower BEERY-visual perception scores (63.5±26.2 vs 92.2±12.5, p=0.01).Conclusion: Increased BMI and BP may contribute to cognitive impairments observed in children with CA. We suggest that a more diffuse mechanism of brain injury is responsible for the specific cognitive impairments associated with increased BMI and BP. Larger controlled studies involving structural and perfusion imaging are needed.
Abstract TP408: Risk Factors for Clinical and Radiographic Progression in Pediatric Moyamoya
- Matsanga Leyila Kaseka,
- Mahmoud Slim and
- Nomazulu Dlamini
Stroke Volume 51, Issue Suppl_1

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Objective: To compare clinical and radiographic evolution of moyamoya disease (MMD) and moyamoya syndrome (MMS).Method: We conducted a retrospective review of a prospectively enrolled cohort of children with moyamoya followed from 2003 to 2018. Patients with a final diagnosis of PHACE syndrome and transient cerebral arteriopathy were excluded. Demographic, clinical and radiographic (MRI) characteristics at diagnosis were obtained. Evidence of clinical evolution (stroke, TIA) or radiographic progression were assessed on subsequent clinical visits and neuroimaging, respectively. We compared the frequency and time to clinical and radiographic progression prior to revascularization surgery between MMD and MMS (including specific etiologies, namely neurofibromatosis [NF1] and sickle cell disease [SCD]). Comparisons were conducted using independent t or chi-square tests, as appropriate.Results: Ninety-three patients were identified, of whom 37 had MMD and 56 had MMS (20 NF1, 20 SCD and 16 others etiologies). The median age at presentation was 8.31 years (IQR 5.03-10.87) and the median follow up time was 5 years ( IQR 2-8). MMD were at greater risk of a recurrent ischemic event (52% MMD vs 42% MMS, p=0.049), but no difference was noted between MMD, NF1 and SCD. The risk of ischemic event recurrence was significantly higher among patients who presented with TIA at diagnosis (79.26% vs 21%, p <0.0001), an advanced Suzuki stage (59% with Suzuki 3-6 vs 28% Suzuki with 1-3, p= 0.009) and bilateral moyamoya (47% vs 21.95% with unilateral, p=0.012). No difference was noted between groups regarding the median time to radiographic progression. Radiographic progression was more likely among younger children (50% if less 10 years vs 21% if more than 10 years, p= 0.0085) and children presenting with TIA (53% vs 34%, p=0.038).Conclusions: TIA at presentation, advance Suzuki stage, and bilateral disease conferred greater ischemic risk among children with moyamoya. Vasculopathy progression was more likely among young patients and those with TIA at presentation.
Abstract 2420: Effect of Rosiglitazone on Left Ventricular Systolic and Diastolic Function and on NT-proBNP: Results of the Echocardiographic and Biomarker Substudy of the DREAM Trial
- Mahmoud A Sharaf,
- Mahadevan Rajaram,
- Patrick Sheridan,
- Gilles Dagenais,
- Raphael Diaz,
- Salim Yusuf,
- Herztel C Gerstein and
- Eva Lonn
Circulation Volume 118, Issue suppl_1828 October 2008

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Objectives: Thiazolidinediones increase the risk of heart failure (HF). To study mechanisms, we evaluated the effects of rosiglitazone on LV systolic function (LVSF), LV volumes, LV diastolic function (LVDF) and NT-proBNP.Methods: DREAM was a large placebo-controlled trial of rosiglitazone in people with impaired glucose tolerance and/or impaired fasting glucose, but without cardiovascular disease. In a subset of 332 DREAM trial participants, echocardiograms were obtained after a median of 3 years post randomization and NT-proBNP was measured at baseline and after 3 years. LV ejection fraction (LVEF), fractional shortening (FS), wall motion score index (WMSI), LV end-systolic (LVESV) and end-diastolic volume (LVEDV), LV mass index (LVMI), realtive wall thickness (RWT), left atrial volume index (LAVI), LVDF grade (derived from pulsed-wave mitral inflow and pulmonary vein Doppler, mitral annular tissue Doppler and LAVI) and changes from baseline in plasma NT-pro-BNP (Δ NT-proBNP) were compared between participants assigned to rosiglitazone and placebo.Results: Participants’ mean age was 55 years, 60% were female and baseline blood pressure was 138/84 mmHg. There were no significant differences in any baseline characteristics between the study groups.Three years post-randomization participants in the rosiglitazone group had higher LVESV, LVEDV, LVMI, LAVI and advanced LV diastolic dysfunction, but LVEF, FS and WMSI did not differ between the study groups. NT-proBNP increased significantly more in the rosiglitazone vs. the placebo group.Conclusions: Rosiglitazone causes abnormalities in LVDF, LV volumes and NT-proBNP (probably due to fluid retention), but does not cause LVSF impairment, suggesting no adverse effects on LV contractility. Measures of LV systolic, diastolic function and NT-pro-BNP in the Rosiglitazone and Placebo Groups
Abstract 110: Lactate and Hypotension as Predictors of Mortality After In-Hospital Cardiac Arrest
- Mahmoud S Issa,
- Tuyen Yankama,
- Het Patel,
- Lethu Ntshinga,
- Amin Coker,
- Anne V Grossestreuer,
- Michael Donnino and
- Katherine Berg
Circulation Volume 140, Issue Suppl_219 November 2019

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Background: In hospital cardiac arrest (IHCA) affects >290,000 people in USA annually. Although there are many differences between IHCA and out of hospital cardiac arrest (OHCA), the bulk of data used to guide management comes from OHCA studies. Prediction of mortality after IHCA could be useful in making decisions around post-arrest care. We hypothesized that elevated lactate and the need for vasopressor support after arrest would predict mortality in an IHCA population.Methods: Retrospective single-center observational study of all adult IHCA patients with sustained return of spontaneous circulation (ROSC), lactate within 2 hrs of ROSC, and intubated pre-arrest or within 1 hr after, from 2008 - 2018. Multivariable logistic regression was used to evaluate the association of post-ROSC lactate and need for vasopressors, as well as other covariates, with mortality. Backwards selection was used to determine the most parsimonious model.Results: Of 541 patients; 364 met criteria and were included. Overall mortality was 56%. The distributions of initial rhythm, pre-arrest vasopressor and pre-arrest mechanical ventilation were similar between groups. Patients who received vasopressors within 3 hrs of ROSC had higher mortality compared to patients who did not (58% vs. 43%, p-value 0.04). Elevated lactate level was also associated with mortality (44% if < 5 mmol/L, 58% if 5 - 10 mmol/L, and 73% if ≥10 mmol/L, p-value<0.01). Mortality in those with lactate <5 and no vasopressors was 33%, compared to 75% in those with lactate >10 and need for vasopressors (p<0.01). The most parsimonious predictive model included lactate, post-arrest vasopressor, age, arrest location, and pre-arrest diagnosis (AUC 0.68 [95 CI: 0.63-0.74]).Conclusion: Post-ROSC lactate and need for vasopressor were useful predictors of mortality, although AUC was lower than what has been reported in OHCA studies. Development of a more discriminating tool would be valuable to clinicians and in IHCA research.
Abstract 19639: The Pulse Pressure Stress Index: A Simple and Novel Exercise-Based Risk Factor for Adverse Cardiovascular Outcomes. Results From the Henry Ford ExercIse Testing (FIT) Project
- Mahmoud S Al Rifai,
- John McEvoy,
- Michael Blaha,
- Clinton Brawner,
- Al Mallah Mouaz,
- Steven Keteyian and
- Jonathan K Ehrman
Circulation Volume 136, Issue suppl_114 November 2017

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Introduction: Pulse pressure (PP) is directly influenced by cardiac output and, hence, changes with physical activity. To our knowledge, no study has evaluated the prognostic significance of PP response to exercise. We studied the relationship between a novel parameter, the pulse pressure stress index (PPSI), and adverse outcomes in a large clinical registry of adults who were referred for exercise treadmill stress testing.Hypothesis: Poor PP response to exercise is inversely associated with risk of incident MI or death.Methods: The PPSI was calculated as PP at peak exercise divided by resting PP and was analyzed categorically (by quartile) and continuously (per 1 unit increase). Multivariable-adjusted Cox proportional hazards models examined the association between baseline PPSI and risk of future myocardial infarction (MI), or mortality.Results: Among 58,660 FIT participants referred for stress testing without prior MI, mean (SD) age was 53 (13) years, 51% were men, and 29% black. A total of 1,734 incident MI and 6,829 mortality events occurred after a mean (SD) follow-up of 6.1 (4.3) and 11.0 (4.6) years, respectively. There was a graded and monotonic lower risk of events with higher PPSI achieved. For example, compared to quartile 1, the 4^th quartile of PPSI was associated with a 12% (95% CI 1%, 39%) lower risk of MI and 31% (95% CI 12%, 40%) lower risk of mortality (TABLE).Conclusions: An inverse association exists between PP response to exercise and risk of adverse events. Low PP response to exercise may be considered a novel, independent, and readily quantifiable high-risk feature derived from exercise stress testing.
Abstract P584: Sleep in Pediatric Stroke Study (SleePSS): Neuroimaging and Neurocognitive Correlates of Sleep Health in Pediatric Stroke
- Mahmoud Slim,
- Robyn Westmacott,
- Anissa Mumin,
- INDRA NARANG,
- Shelly Weiss,
- Mahendranath d Moharir,
- Liza Pulcine,
- Daune MacGregor,
- Gabrielle A DEVEBER and
- Nomazulu Dlamini
Stroke Volume 52, Issue Suppl_11 March 2021

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Introduction: Pediatric arterial ischemic stroke (AIS) is a serious cause of lifelong neurological and cognitive disabilities. Although they are at increased risk of obstructive sleep apnea (OSA), children with AIS may have abnormal sleep indices even in the absence of OSA diagnosis. This can adversely affect their blood vessels health (impaired cerebrovascular reactivity, CVR) and can lead to neurocognitive impairments. Therefore, we aimed to investigate the association of cerebral blood vessels health with polysomnographic measures and cognitive function in children with AIS.Hypothesis: Quantitative measure of negative CVR, i.e. fractional negativity (fneg) and negative CVR correlate significantly with abnormal overnight oxygen and carbon dioxide levels in children with AIS, even in the absence of OSA.Methods: We conducted a single-centre cross-sectional study in children with AIS aged between 8 and 18 years old and who were not at risk of OSA (i.e., pediatric sleep questionnaire score<0.33). All children were evaluated using:(1) Non-invasive Blood Oxygen Level Dependent magnetic resonance imaging to study CVR.(2) An overnight polysomnography(3) Comprehensive evaluation of intellectual abilities, attention and executive function.Results: Ten children with AIS (40% males; median age: 14.3 years) were included after a median of 8.8 years following stroke onset. None of the children was diagnosed with OSA. We found significant correlations between fneg and minimum oxygen saturation during REM sleep (r=0.81, r=0.68 and r=0.76 in grey matter, white matter and whole brain, respectively; p<0.05). The whole brain mean negative CVR correlated significantly with the visual spatial, fluid reasoning, and emotion regulation indices (r=-0.82, -0.8, and 0.75, respectively, p<0.05). Mean negative CVR in white matter correlated significantly with the indices of executive function (emotion regulation, cognitive regulation and global executive composite scores, r=0.72-0.76, p<0.05).Conclusion: Impaired CVR in children with AIS correlates with abnormal sleep indices even in the absence of OSA diagnosis. This can potentially result in cognitive difficulties, the majority of which remain not fully explained by stroke-related factors.
Abstract 11913: The Prognostic Impact of Congestive Heart Failure on Peripheral Artery Disease Intervention Outcomes: Nationwide Insight
- Abdalla Hassan,
- Ashraf Abugroun,
- Hussein Daoud,
- Shafaq Mahmoud and
- Alvaro Alonso
Circulation Volume 140, Issue Suppl_119 November 2019

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Background: The impact of coronary artery disease on patients with peripheral artery disease (PAD) has been thoroughly investigated. However, the effect of congestive heart failure (CHF) history on PAD intervention outcomes is yet to be defined and this is what we aimed to evaluate.Methods: We queried the National Inpatient Sample Database (NIS) and identified 31,985 patients (pts) who presented with acute or symptomatic chronic limb ischemia (CLI) requiring transcatheter non-surgical peripheral intervention in the year of 2016. We divided them into 2 groups based on CHF history (Hx). Primary outcomes were major adverse cardiovascular events (MACE) including in-hospital mortality, MI, stroke, bleeding, and shock. Secondary outcomes were renal and respiratory failure, length of stay and total cost.Results: CHF Hx was present in 6,480 pts (20.3%). Mean age was 68.8±11.9 years. Females constituted 42.8%. Pts with CHF Hx had significantly higher rates of in-hospital mortality (3.6% vs 1.3%), acute MI (4.7% vs 1.3%), stroke (0.9% vs 0.5%), cardiogenic shock (1.3% vs 0.5%), and respiratory and renal failure (7.5% vs 2.0% & 27.1% vs 11.2%; respectively)[p <0.001]. On the other side, pts with no prior CHF hx had significantly shorter length of stay (4 vs 7 days) and lower cost (89,400 vs 110,500 USD). On multivariate logistic regression analysis, the presence of CHF was an independent predictor of in-hospital mortality (adjusted OR= 1.9; p=0.01), acute MI (adjusted OR=2.4; p<0.001), renal and respiratory failure (adjusted OR=1.8 and 3 [p<0.001], respectively), and bleeding (adjuster OR=1.4; P<0.001). Interestingly, cardiogenic shock and stroke were not particularly associated with CHF Hx.Conclusion: CHF is a poor prognostic indicator in pts presenting with acute or symptomatic CLI requiring transcatheter intervention. Given their higher risk profile and lower ischemic threshold, earlier intervention might of a higher value in this specific population.
Abstract 11914: Sex Differences and Impact on Peripheral Artery Disease Intervention Outcomes From a Nationwide Data: More Significant Than We Think
- Abdalla Hassan,
- Ashraf Abugroun,
- Hussein Daoud,
- Shafaq Mahmoud and
- Alvaro Alonso
Circulation Volume 140, Issue Suppl_119 November 2019

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Background: Females have been linked to potential higher risk of peripheral artery disease (PAD) complications, however, sex differences in PAD minimally invasive intervention outcomes remain to be identified and this is what we aimed to examine.Methods: We queried the National Inpatient Sample Database (NIS) and identified 31,975 patients (pts) who presented with acute or symptomatic chronic limb ischemia (CLI) requiring transcatheter non-surgical peripheral intervention in the year of 2016. We divided them into 2 groups based on their sex. Primary outcomes were major adverse cardiovascular events (MACE) including in-hospital mortality, acute MI, stroke, bleeding, and shock. Secondary outcomes were renal and respiratory failure, length of stay and total cost.Results: Mean age was 68.8±11.9 years. Males constituted 57.2%. Females had significantly higher rates of in-hospital mortality (2.1% vs 1.5%), acute MI (2.2% vs 1.8%), stroke (1.0% vs 0.4%), cardiogenic shock (0.8% vs 0.5%), respiratory failure (3.7 vs 2.7%), and prolonged hospital stay (5 vs 4 days) [p <0.001]. No significant difference was found in the incidence of acute renal failure or overall admission cost [14.4% and 93,300 USD; respectively]. On multivariate logistic regression analysis, after adjusting for age and baseline clinical characteristics, female sex was an independent predictor of stroke (adjusted OR=2.79; p<0.001), the composite risk of MACE (adjusted OR=1.65; <0.001), acute MI (adjusted OR=1.5; p<0.001), respiratory failure (adjusted OR=1.4; p=0.02), and bleeding (adjusted OR=1.4; P<0.001). Interestingly, cardiogenic shock and length of stay were not associated with pts’ sex.Conclusion: Females presenting with acute or symptomatic CLI requiring transcatheter peripheral intervention have a significantly higher composite risk of MACE. Accordingly, patient education and earlier intervention are particularly needed among women with PAD.
Abstract 12598: Impact of Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease on Systemic Inflammation and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA)
- Mahmoud S Al Rifai,
- Michael J Blaha,
- Roger S Blumenthal,
- Michael G Silverman,
- Khurram Nasir,
- Matthew J Budoff and
- Ron Blankstein
Circulation Volume 130, Issue suppl_225 November 2014

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Introduction: We sought to characterize the association of three adiposity-related risk factors - obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) - with the outcomes of increased inflammation and subclinical atherosclerosis.Methods: We conducted a cross-sectional analysis of 3976 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with adequate CT imaging to diagnose NAFLD. For the study exposures, obesity was defined as BMI ≥30 kg/m², metabolic syndrome by ATP III criteria, and NAFLD using non-contrast cardiac CT and a liver/spleen attenuation ratio (L/S) 0. In order to assess for a possible gradient-response, adjusted logistic regression was used to examine the association of a stepwise increase in the number of three adiposity-related risk factors with increased inflammation and subclinical atherosclerosis. Additional models were conducted stratifying by gender or ethnicity.Results: Mean age of participants was 63 years, 45% were male, 37% were white, 10% Chinese, 30% African American, and 23% Hispanic. NAFLD was associated with an odds ratio for high hs-CRP and CAC>0 of 1.54 (1.27-1.87) and 1.41 (1.15-1.73), respectively, adjusting for obesity, metabolic syndrome and traditional risk factors. There was a positive interaction between female gender and NAFLD in the association with high hs-CRP (p=0.01). There was no interaction by race. Importantly, with increasing number of adiposity-related risk factors, the odds ratios of high hs-CRP and CAC>0 increased in a graded fashion, suggesting a collective association (Figure).Conclusion: There is an association between three adiposity-related risk factors - obesity, metabolic syndrome, and NAFLD - with both increased inflammation and subclinical coronary atherosclerosis.
Abstract P1044: A Drug-Like Activity Of Polydopamine Nanoparticles Mediates Cardiomyocyte Bio-Modulation And Maturation
- Syed Baseeruddin Alvi,
- Divya Sridharan,
- Mahmoud Shalaan,
- muhamad mergaye and
- Mahmood Khan
Circulation Research Volume 131, Issue Suppl_15 August 2022

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Introduction: Bio-active nanomaterials are being extensively explored for various biomedical and tissue engineering applications. Polydopamine nanoparticles (PDA-NPs) is a self-assemble polymer derived from dopamine which has demonstrated anti-inflammatory potential by modulating immune cells. The use of PDA-NPs as bio-active nanomaterial for cardiac tissue repair/regeneration warrants further exploration.Hypothesis: We hypothesize that the polydopamine nanoparticles could modulate cardiomyocyte activity due to the presence of catechol moieties and may alter the gene expression and promote maturation of cardiomyocyte.Results: The PDA-NPs were fabricated by oxidative polymerization of dopamine monomers which resulted in formation of spherical nanoparticles. These nanoparticles were in the range of 100- 200 nm as evident from SEM and TEM imaging. The FTIR analysis of PDA-NPs revealed the characteristic peaks confirming the presence of quinone and catechol groups. These functional groups play important role in surface adhesion, thus imparting adhesive properties to PDA-NPs. The PDA-NPs were exposed to human iPSC-derived cardiomyocytes (HiPSC-CMs) and their real-time activity was monitored by using MEA. An instantaneous change in the beat period of cardiomyocytes was observed in a dose dependent manner. Moreover, a significant shortening in field potential duration was also seen, these finding suggest that the PDA-NPs stimulates the cardiomyocytes through catechol groups thereby exhibiting strong adrenergic effect. These finding demonstrates that PDA-NPs could significantly modulate the contractility of cardiomyocytes and could be used for enhancing cardiac contractility. Furthermore, prolonged incubation of PDA-NPs showed accumulation in the perinuclear region as revealed by fluorescence imaging. The influence of intracellular accumulation of PDA-NPs on gene expression was assessed by qRT-PCR. A significant increase in MYL2/MYL7 ratio, GJA5 and TNNI3 was noted, demonstrating the maturation of cardiomyocytes.Conclusion: Overall, the treatment of hiPSC-CMs cardiomyocytes with PDA-NPs shows dual response, primarily by modulating the contractility in a dose dependent manner and secondary by promoting maturation.
Abstract 3485: Changes in Fasting Glucose During Hospitalization and Long-Term Mortality in Patients with Acute Myocardial Infarction
- Doron Aronson,
- Haim Hammerman,
- Michael Kapeliovich,
- Rafael Beyar,
- Walter Markiewicz and
- Mahmoud Suleiman
Circulation Volume 114, Issue suppl_1831 October 2006

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Introduction: Elevated fasting glucose (FG) on admission is associated with increased short-term mortality in patients with acute myocardial infarction (AMI). However, no data is available with regard to changes in FG during hospital stay and post discharge outcome.Methods: We prospectively studied 1002 nondiabetic patients (pts) presenting with AMI. FG was obtained at admission (AFG) and prior to discharge (DFG). The pts were categorized into 4 groups:1) normal (<110 mg/dL) AFG and DFG (n = 504), 2) elevated (>110 mg/dL) AFG normal DFG n = 221), 3) normal AFG and elevated DFG (n = 86) and 4) elevated AFG and DFG (n = 191). Cox proportional hazards analyses were performed to determine the relation between categories of FG and mortality adjusting for age, creatinine, hypertension, smoking, Killip class, systolic blood pressure and heart rate on admission, anterior infarction, previous MI, reperfusion therapy and ejection fraction.Results: The median follow-up after hospital discharge was 24 months. Kaplan-Meier survival curves according to AFG and DFG is shown in the Figure. Pts with normal AFG and DFG had the lowest mortality. Pts with elevated AFG had an increased mortality even if their DFG returned to normal level (HR 2.7; 95% CI 1.6–7.4, P = 0.0003). Mortality was also increased in pts with normal AFG who developed elevated DFG (HR 2.71 95% CI 1.0–4.7, P = 0.045). Pts with persistent elevation of FG incurred the highest mortality (HR 5.3; 95% CI 3.3–8.6, P < 0.0001).Conclusion: FG during hospital stay is a strong independent predictor of long-term mortality after hospital discharge. Even a transient elevation in FG portends increased long-term mortality.
Abstract 12045: Gender Differences in Medicare Payments Among Female and Male Cardiologists
- Inbar Raber,
- Cian P McCarthy,
- Mahmoud S Al Rifai and
- John W McEvoy
Circulation Volume 140, Issue Suppl_119 November 2019

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Introduction: A wage gap exists among male and female physicians in cardiology. It is unknown how differences in clinical productivity and reimbursements from Centers for Medicare & Medicaid Services (CMS) might contribute to this wage gap.Hypothesis: Gender differences exist in the charges submitted to and reimbursements received from CMS among men and women in cardiology.Methods: In this cross-sectional analysis, we obtained Medicare charges and reimbursement data among CMS cardiologists in 2016 using the ‘CMS: Medicare Provider Utilization and Payment Data’ database. We evaluated the gender distribution of Medicare charges and reimbursements among cardiologists. Mean, median, and maximum charges and reimbursements were calculated for male and female cardiologists and differences were compared using Kruskal-Wallis testing.Results: In 2016, there were 17,524 cardiologists who received reimbursements from CMS in a facility-based setting and 16,929 who received reimbursements in a non-facility-based setting. Women accounted for 13% of the work-force in either practice setting and received 9.3% and 8.1% of the CMS reimbursements in facility-based and non-facility-based settings, respectively. On average, men also submitted more Medicare charges in facility (1,543±1,471 vs 1,249±1,181, p<0.001) and non-facility-based settings (2,709±4,085 vs 1,520±2,308, p<0.001). Men received higher mean payments in both facility ($77,421±$68,461 vs $53,192±$44,743, p<0.001) and non-facility-based settings ($157,425±$232,552 vs $95,119±$130,411, p<0.001). (Figure) A sensitivity analysis showed that these trends were consistent among general cardiologists, electrophysiologists, and interventional cardiologists.Conclusion: Men submit more CMS charges and receive higher CMS payments compared to women in cardiology. Further evaluation is needed to understand the reason for this difference.
Abstract WMP118: The Association Between Sleep Related Breathing Disorders and Neuropsychological Function in Pediatric Stroke
- Mahmoud Slim,
- Robyn Westmacott,
- Elena Grbac,
- Sandra Toutounji,
- Indra Narang,
- Shelly Weiss,
- Ann-Marie Pontigon,
- Jaspal Singh,
- Kathleen Andres,
- Daune MacGregor,
- Gabrielle deVeber,
- Mahendranath Moharir and
- Nomazulu Dlamini
Stroke Volume 50, Issue Suppl_1

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Introduction: Sleep-related breathing disorders (SRBDs) in childhood are associated with adverse outcomes including developmental and behavioral disorders. The association of SRBDs with pediatric stroke is poorly understood. We aimed to assess the risk of SRBDs in children with stroke or non-stroke high risk arteriopathies (NSA) and to evaluate their association with cognitive and behavioral function.Hypothesis: Children with stroke or NSA have a higher rate of SRBD and associated poor cognitive and behavioral function.Methods: We conducted a cross-sectional study of children with arterial ischemic stroke (AIS), cerebral sinovenous thrombosis (CSVT) and NSA such as moyamoya. All children completed the Pediatric Sleep Questionnaire (PSQ). High risk for SRBDs was defined as a PSQ score ≥0.33. Children completed the Adaptive Behavior Assessment System (ABAS-2) parent and teacher forms and/or The Wechsler Intelligence Scale for Children (WISC-V) within 1 year of completing the PSQ.Results: Overall, 213 were included (54% males, median age: 9 years [IQR 5-14]). Forty-nine children (23%) were at high risk of SRBDs. The risk of SRBDs did not vary with age, gender or stroke subtype: AIS (25%), CSVT (20%), other stroke subtypes (20%) and NSA (24%) (p= 0.8). Children with SRBD had higher mean BMI z-scores (0.9±1.5 vs 0.4±1.3, p=0.06). Twenty-four and 15 children underwent ABAS-2 parent and teacher assessment, respectively. The global adaptive composite scores of both forms significantly correlated with the total PSQ scores (r_s=-0.6, p<0.01 for the parent form and r_s=-0.63, p=0.01 for the teacher form). Correlation coefficients remained statistically significant upon controlling for BMI. In 19 children who completed the WISC-V, those at risk of SRBDs (n=7) had significantly lower Full Scale IQ (70±24.7 vs 91±17, p=0.03), processing speed (55±44 vs 96±19, p=0.02) and working memory (77±23 vs 98±15, p=0.02) compared to children at no risk. Cognitive and behavioral function did not differ across stroke subtypes.Conclusions: Pediatric stroke or NSA is commonly associated with SRBDs which in turn is linked to significant decline in cognitive and behavioral function. Further studies are required to understand the underlying pathological mechanisms.
Abstract 8889: Predictors of 30-Day Readmission in Nonagenarians Presenting With Acute Diastolic Heart Failure: Nationwide Analysis
- Ahmed Maraey,
- Hadeer Elsharnoby,
- Ahmed Elzanaty,
- Ahmed Younes,
- Mahmoud Khalil,
- Mahmoud Salem and
- Nabila Dawoud
Circulation Volume 144, Issue Suppl_116 November 2021

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Background: Acute diastolic heart failure (DHF) is a common but poorly studied diagnosis in hospitalized nonagenarians.Objective: To identify predictors of 30-day readmission in nonagenarians hospitalized with acute DHF.Methods: We queried National Readmission Database (NRD) of years 2016-2018 for patients aged 90 or above admitted with acute or acute on chronic DHF. ICD-10 was used to identify diagnoses. We excluded patients discharged in December and those who died in index admission. Univariate regression was performed on each variable. Variables with p value of < 0.2 were included in our multivariate regression model (figure 1).Results: From a total of 45393 index admissions, 43646 (96.2%) survived to discharge. A total of 7437 (16.4%) patients had a 30-day readmission. Mean cost of readmission was 43265 USD per patient. Significant predictors of 30-day readmission were chronic ischemic heart disease (OR=1.11, 95%CI [1.01-1.22], P=0.023), chronic kidney disease stage 3 or above (OR=1.19, 95%CI [1.07-1.34], P=0.002), complicated diabetes (OR=1.22, 95%CI [1.07-1.38], P=0.003), and length of stay (LOS) > 2 days (OR=1.20, 95% CI [1.09-1.32], P=0.000). Female sex (OR=0.90, 95% CI [0.83-0.99], P=0.030) and palliative care visit (OR=0.27, 95% CI [0.21-0.34], P=0.000) were associated with lower odds of readmission.Conclusion: In nonagenarians hospitalized with acute DHF, 30-day readmission is common and costly. Chronic comorbidities and LOS >2 days were predictors of readmission. Palliative care visit was strongly associated with lower risk of readmission. Further strategies need to be developed to improve the quality of care and prevent readmission in this age group.
Abstract TP182: Association Between Type 2 Myocardial Infarction And 90-day Ischemic Stroke Readmission In Elderly: Insights From National Database
- Hadeer Elsharnoby,
- Ahmed Maraey,
- Waqas Kayani,
- Mahmoud Khalil,
- Mahmoud Salem,
- Hamood Rahman and
- Amir Kichloo
Stroke Volume 53, Issue Suppl_11 February 2022

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Background: Type 2 myocardial infarction (T2MI) is an ischemic myocardial injury in the context of oxygen supply/demand mismatch in the absence of a primary coronary event. Chronic myocardial injury was linked to increased risk of stroke in the long term follow up. However, association between T2MI and stroke in short term follow up is unclear due to limited available data.Objective: To study the impact T2MI on 90-day readmission with ischemic stroke or transient ischemic attack (TIA) in elderly hospitalized patients.Methods: The study is a retrospective analysis of national readmission database (NRD) of year 2018 for patients ≥ 65 years. Patients were excluded if they had stroke, myocardial infarction other than T2MI or prior stroke in index admission. Patients admitted between October and December to allow 90 days follow up. International classification of disease, tenth edition (ICD 10-CM) was used to identify diagnoses. Multivariate logistic regression model was used to calculate adjusted odds ratio (aOR) and adjust for potential confounders (figure 1).Results: A total of 6,643,620 patients were admitted in 2018 that met our criteria. T2MI was present in 88,282 (1.3%) index admissions. A total of 1,549,951 patients were readmitted to the hospital within 90 days of whom 36,981 (2%) patients were diagnosed with stroke or TIA. Patients readmitted with stroke were more likely to be female (56% vs 55%, P=0.005), had complicated hypertension (46% vs 35%, P<0.001), complicated diabetes mellitus (28% vs. 20%, P<0.001), and congestive heart failure (35% vs 26%, P<0.001). T2MI was associated with increased risk of 90-day stroke readmission (aOR: 1.21, 95%CI [1.09-1.35], P<0.001).Conclusion: In our large retrospective study, T2MI was found to be an independent predictor of 90-day readmission with stroke or TIA in hospitalized elderly patients. Further studies are warranted to identify optimum strategy of risk stratification and management of such patient.
Abstract 13347: Oxygen Metabolism After Cardiac Arrest: Patterns and Association With Survival
- Katherine M Berg,
- Lakshman Balaji,
- Mahmoud S Issa,
- Michael W Donnino and
- Anne V Grossestreuer
Circulation Volume 144, Issue Suppl_216 November 2021

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Introduction: How mitochondrial damage from cardiac arrest (CA) and resuscitation affects oxygen metabolism, and whether changes in metabolism are associated with outcome, is not well understood. We previously reported an association between higher oxygen consumption (VO2) in the first 12 hours after return of spontaneous circulation (ROSC) and survival in 17 post-arrest (PA) patients. The present study was conducted to investigate the association of VO2, VCO2 and RQ with survival in a larger PA cohort.Methods: From adult patients enrolled in several CA trials at our center, we selected those receiving targeted temperature management with ≥60 minutes of post-ROSC metabolic data collected in the first 24 hours after ROSC, using a gas exchange monitor that measures continuous VO2, VCO2 and RQ.The area under the curve (AUC) for VO2, VCO2 and RQ was calculated using all available values in the first 12 and 24 hours after ROSC. For both time periods, logistic regression was used to describe the relationship between survival and each AUC. We adjusted for temperature, sedation, and vasopressors. Hourly medians were plotted by survival.Results: Of 64 patients included, 32 (50%) survived. There was no significant association between survival and AUC-VO2 or AUC-VCO2 in the first 12 (n=43) or 24 (n=64) hours after ROSC. 21 (49%) had a median RQ <0.7 in the first 12 hours, and there was an association between survival and AUC-RQ in this time period (see table).Conclusion: There were no significant associations between VO2, VCO2 and survival in the first 12 and 24 hours after ROSC. RQ was abnormally low in many patients, and higher RQ in the first 12 hours after ROSC was associated with survival.
Abstract 205: Role of AT1a Receptor in Cardiac Function and Acid Base Homeostasis during Exercise Endurance
- Ahmad M Alhajoj,
- Mahmoud S Alghamri,
- Roberta L Pohlman,
- Nadja Grobe,
- Debora Nakamoto and
- Mariana Morris
Hypertension Volume 62, Issue suppl_11 September 2013

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Angiotensin Type 1 (AT1) receptors are involved in cardiovascular pathology. Lozartan, the AT1 receptor blocker, in combination with exercise has been shown to be effective in improving cardiac performance. The goal of the study was to investigate the role of AT1a receptors on cardiac function, and exercise tolerance in response to aerobic exercise using AT1a receptor knockout (AT1aKO) mice. An exercise wheel system was used for the exercise paradigm. Male (C57BL/6) wild type (WT) and AT1aKO mice were randomly assigned to four groups: WT control (n=6), WT exercise (WTEX, n=8), AT1a KO (KO) control (n=5), and AT1a KO exercise (KOEX, n=8). Mice were forced to run at a velocity of 8 m/min for 1 hour, 3d/wk, for 7 wks. Echocardiography was conducted at baseline and 7 wks. Lactate was measured during several exercise sessions. Electrolytes and cardiac histology were assessed post-sacrifice. Results showed a significant increase in ejection fraction (EF%) in KOEX (72.5±1.5%) vs. WTEX and KO control (63.4±1.2% and 63.2±2.2%, respectively). Mitral valve assessment revealed a marked decrease in E-wave velocity in WTEX compared to WT control at baseline (74±1.9 vs.90±3.5 cm/s, p<0.05), while E/A wave ratio remained unchanged. Cardiomyocyte diameter was larger in WTEX compared to KOEX (29.5±0.7 vs. 25.8±0.5 μm, p<0.05). Heart to body weight ratio was significantly higher in WTEX vs. KOEX (5.5±0.2 vs. 4.3±0.1 mg/g, p<0.001). Masson’s Trichrome staining revealed higher collagen levels in WTEX myocardium compared to WT control and KOEX (16% vs. 5%). Blood lactate accumulation values were greater at 5 and 60 min of wheel running in WTEX (4.2±0.4 and 3.9±0.5 mmol/l) vs. KOEX (3.0±0.2 and 2.9±0.2 mmol/l). A basic metabolic panel revealed higher [HCO₃^-] in KOEX vs. WTEX (21.7±0.6 vs. 13.7±1.8 mmol/l). Cl^- was lower in KOEX compared to WTEX (102.5±2.5 vs. 113.5±2.7mmol/l, p<0.05). In conclusion, AT1aKO mice exhibited improved cardiac performance without myocardium hypertrophy, greater exercise endurance, and enhanced metabolic activity in response to chronic exercise. These results suggest that the AT1a receptor is an important mediator of exercise induced cardiac dysfunction and acid-base imbalance during exercise training.
Abstract 8910: Clinical Use, Diagnostic Efficiency and Impact on Patient Management of Cardiovascular Magnetic Resonance
Circulation Volume 124, Issue suppl_2122 November 2011

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Objectives: To evaluate the clinical use, diagnostic efficiency and impact on patient management of cardiovascular magnetic resonance (CMR).Methods: Data of the individual patient and procedural information of 2598 consecutive clinically indicated CMR exams were collected. For a representative subgroup of 250 exams, an external blinded reviewer evaluated the need for diagnostic tests and hospitalization before and after CMR and assessed the impact of CMR on patient management.Results: Table 1 lists the subjects' characteristics and procedural information of all studies. CMR was used in a large variety of indications, with inflammatory (29.4 %) and ischemic (26.2 %) heart disease as the most frequent. All moderate adverse events (0.5 %) were associated with stress medication or contrast media. In the subgroup analysis, CMR ruled out a suspected disease in 63.1%, confirmed a suspected or known disease in 27.8% or detected an unexpected new pathology in 7.2 %. The clinical question was answered completely or partial in 88.4 % and 11.2 %, respectively. CMR reduced the amount of ordered diagnostic tests by 65.7 % and led to an altered diagnostic strategy in the individual patient in 92.4 %. Heart catheterization was cancelled in almost every third patient following CMR (11 / 36), and newly ordered after CMR in additional 6% (12 / 214). In 23.6 %, CMR led to a strategic change between in- or outpatient treatment.Conclusions: CMR is safe, robust and versatile. It influences the indication for hospital admission, the choice and extent of individual downstream diagnostic testing, and the determination of the final diagnosis.

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