Rajesh Dash, MD PhD; Director of SSATHI & CardioClick

All Publications

• Sociodemographic disparities in the use of cardiovascular ambulatory care and telemedicine during the COVID-19 pandemic. American heart journal Osmanlliu, E., Kalwani, N. M., Parameswaran, V., Qureshi, L., Dash, R., Scheinker, D., Rodriguez, F. 2023

  Abstract

  The COVID-19 pandemic accelerated adoption of telemedicine in cardiology clinics. Early in the pandemic, there were sociodemographic disparities in telemedicine use. It is unknown if these disparities persisted and whether they were associated with changes in the population of patients accessing care.We examined all adult cardiology visits at an academic and an affiliated community practice in Northern California from March 2019 to February 2020 (pre-COVID) and March 2020 to February 2021 (COVID). We compared patient sociodemographic characteristics between these periods. We used logistic regression to assess the association of patient/visit characteristics with visit modality (in-person vs telemedicine and video- vs phone-based telemedicine) during the COVID period.There were 54,948 pre-COVID and 58,940 COVID visits. Telemedicine use increased from <1% to 70.7% of visits (49.7% video, 21.0% phone) during the COVID period. Patient sociodemographic characteristics were similar during both periods. In adjusted analyses, visits for patients from some sociodemographic groups were less likely to be delivered by telemedicine, and when delivered by telemedicine, were less likely to be delivered by video versus phone. The observed disparities in the use of video-based telemedicine were greatest for patients aged ≥80 years (vs age <60, OR 0.24, 95% CI 0.21, 0.28), Black patients (vs non-Hispanic White, OR 0.64, 95% CI 0.56, 0.74), patients with limited English proficiency (vs English proficient, OR 0.52, 95% CI 0.46-0.59), and those on Medicaid (vs privately insured, OR 0.47, 95% CI 0.41-0.54).During the first year of the pandemic, the sociodemographic characteristics of patients receiving cardiovascular care remained stable, but the modality of care diverged across groups. There were differences in the use of telemedicine vs in-person care and most notably in the use of video- vs phone-based telemedicine. Future studies should examine barriers and outcomes in digital healthcare access across diverse patient groups.

  View details for DOI 10.1016/j.ahj.2023.06.011

  View details for PubMedID 37369269

  View details for PubMedCentralID PMC10290766

• Clinical programs for cardiometabolic health for South Asian patients in the United States: A review of key program components. Health sciences review (Oxford, England) Gulati, R. K., Husaini, M., Dash, R., Patel, J., Shah, N. S. 2023; 7

  Abstract

  Medical literature shows that South Asians have approximately a 2-fold higher risk of atherosclerotic cardiovascular disease (CVD) compared with other populations. Given this high prevalence, clinical programs to promote cardiovascular health have emerged in the United States that are dedicated to clinical care for South Asian individuals. In this review, we have summarized the key characteristics of clinical programs in the U.S. dedicated to preventing and managing CVD in South Asian American patients. These clinical centers have many unique components in common that are catered to South Asian patient populations including ethnicity concordance of clinical providers, intensive cardiovascular screening protocols with laboratory studies and potentially genetic testing, dieticians and nutritionists who are familiar with South Asian-style dietary patterns, health coaches to support behavior change, community outreach programs, and involvement in clinical research to learn further about risk factors, prevention, and treatment of cardiovascular disease in South Asian populations. There are still many evidence and programmatic gaps left to uncover in the prevention, diagnosis, and management of CVD in South Asian. This review provides guidance for important features, barriers, and facilitators for future cardiovascular centers to develop in the United States where they can serve South Asian populations.

  View details for DOI 10.1016/j.hsr.2023.100093

  View details for PubMedID 37275679

  View details for PubMedCentralID PMC10237508

• Underutilization Of Guideline-directed Genetic Testing In Cardiomyopathies: A Missed Opportunity Longoni, M., Ward, A., Bhasin, K., Lee, D., Bhatt, S., Rodriguez, F., Dash, R. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2023: 704-705

  View details for Web of Science ID 001009258900393

• PERSISTENT SOCIODEMOGRAPHIC DISPARITIES IN CARDIOVASCULAR TELEMEDICINE USE DURING THE COVID-19 PANDEMIC Kalwani, N., Osmanlliu, E., Parameswaran, V., Qureshi, L., Dash, R., Scheinker, D., Rodriguez, F. ELSEVIER SCIENCE INC. 2023: 2287

  View details for Web of Science ID 000990866102298

• Sociodemographic determinants of oral anticoagulant prescription in patients with atrial fibrillations: findings from the PINNACLE registry using machine learning. Heart rhythm O2 Azizi, Z., Ward, A. T., Lee, D. J., Gad, S. S., Bhasin, K., Beetel, R. J., Ferreira, T., Shankar, S., Rumsfeld, J. S., Harrington, R. A., Virani, S. S., Gluckman, T. J., Dash, R., Rodriguez, F. 2023; 4 (3): 158-168

  Abstract

  Current risk scores that are solely based on clinical factors have shown modest predictive ability for understanding of factors associated with gaps in real-world prescription of oral anticoagulation (OAC) in patients with atrial fibrillation (AF).In this study, we sought to identify the role of social and geographic determinants, beyond clinical factors associated with variation in OAC prescriptions using a large national registry of ambulatory patients with AF.Between January 2017 and June 2018, we identified patients with AF from the American College of Cardiology PINNACLE (Practice Innovation and Clinical Excellence) Registry. We examined associations between patient and site-of-care factors and prescription of OAC across U.S. counties. Several machine learning (ML) methods were used to identify factors associated with OAC prescription.Among 864,339 patients with AF, 586,560 (68%) were prescribed OAC. County OAC prescription rates ranged from 26.8% to 93%, with higher OAC use in the Western United States. Supervised ML analysis in predicting likelihood of OAC prescriptions and identified a rank order of patient features associated with OAC prescription. In the ML models, in addition to clinical factors, medication use (aspirin, antihypertensives, antiarrhythmic agents, lipid modifying agents), and age, household income, clinic size, and U.S. region were among the most important predictors of an OAC prescription.In a contemporary, national cohort of patients with AF underuse of OAC remains high, with notable geographic variation. Our results demonstrated the role of several important demographic and socioeconomic factors in underutilization of OAC in patients with AF.

  View details for DOI 10.1016/j.hroo.2022.11.004

  View details for PubMedID 36993910

  View details for PubMedCentralID PMC10041076

• Pandemic-proof recruitment and engagement in a fully decentralized trial in atrial fibrillation patients (DeTAP). NPJ digital medicine Sarraju, A., Seninger, C., Parameswaran, V., Petlura, C., Bazouzi, T., Josan, K., Grewal, U., Viethen, T., Mundl, H., Luithle, J., Basobas, L., Touros, A., Senior, M. J., De Lombaert, K., Mahaffey, K. W., Turakhia, M. P., Dash, R. 2022; 5 (1): 80

  Abstract

  The Coronavirus Disease 2019 (COVID-19) pandemic curtailed clinical trial activity. Decentralized clinical trials (DCTs) can expand trial access and reduce exposure risk but their feasibility remains uncertain. We evaluated DCT feasibility for atrial fibrillation (AF) patients on oral anticoagulation (OAC). DeTAP (Decentralized Trial in Afib Patients, NCT04471623) was a 6-month, single-arm, 100% virtual study of 100 AF patients on OAC aged >55 years, recruited traditionally and through social media. Participants enrolled and participated virtually using a mobile application and remote blood pressure (BP) and six-lead electrocardiogram (ECG) sensors. Four engagement-based primary endpoints included changes in pre- versus end-of-study OAC adherence (OACA), and % completion of televisits, surveys, and ECG and BP measurements. Secondary endpoints included survey-based nuisance bleeding and patient feedback. 100 subjects (mean age 70 years, 44% women, 90% White) were recruited in 28 days (traditional: 6 pts; social media: 94 pts in 12 days with >300 waitlisted). Study engagement was high: 91% televisits, 85% surveys, and 99% ECG and 99% BP measurement completion. OACA was unchanged at 6 months (baseline: 97 ± 9%, 6 months: 96 ± 15%, p = 0.39). In patients with low baseline OACA (<90%), there was significant 6-month improvement (85 ± 16% to 96 ± 6%, p < 0.01). 86% of respondents (69/80) expressed willingness to continue in a longer trial. The DeTAP study demonstrated rapid recruitment, high engagement, and physiologic reporting via the integration of digital technologies and dedicated study coordination. These findings may inform DCT designs for future cardiovascular trials.

  View details for DOI 10.1038/s41746-022-00622-9

  View details for PubMedID 35764796

• DRIVERS OF VARIATION IN TELEMEDICINE USE AT AN ACADEMIC CARDIOVASCULAR CENTER DURING THE COVID-19 PANDEMIC Koos, H., Parameswaran, V., Claire, S., Chen, C., Kalwani, N., Osmanlliu, E., Dash, R., Scheinker, D., Rodriguez, F. ELSEVIER SCIENCE INC. 2022: 2046

  View details for Web of Science ID 000781026602247

• Changes in telemedicine use and ambulatory visit volumes at a multispecialty cardiovascular center during the COVID-19 pandemic. Journal of telemedicine and telecare Kalwani, N. M., Osmanlliu, E., Parameswaran, V., Qureshi, L., Dash, R., Heidenreich, P. A., Scheinker, D., Rodriguez, F. 1800: 1357633X211073428

  Abstract

  Early in the COVID-19 pandemic, cardiology clinics rapidly implemented telemedicine to maintain access to care. Little is known about subsequent trends in telemedicine use and visit volumes across cardiology subspecialties. We conducted a retrospective cohort study including all patients with ambulatory visits at a multispecialty cardiovascular center in Northern California from March 2019 to February 2020 (pre-COVID) and March 2020 to February 2021 (COVID). Telemedicine use increased from 3.5% of visits (1200/33,976) during the pre-COVID period to 63.0% (21,251/33,706) during the COVID period. Visit volumes were below pre-COVID levels from March to May 2020 but exceeded pre-COVID levels after June 2020, including when local COVID-19 cases peaked. Telemedicine use was above 75% of visits in all cardiology subspecialties in April 2020 and stabilized at rates ranging from over 95% in electrophysiology to under 25% in heart transplant and vascular medicine. From June 2020 to February 2021, subspecialties delivering a greater percentage of visits through telemedicine experienced larger increases in new patient visits (r=0.81, p=0.029). Telemedicine can be used to deliver a significant proportion of outpatient cardiovascular care though utilization varies across subspecialties. Higher rates of telemedicine adoption may increase access to care in cardiology clinics.

  View details for DOI 10.1177/1357633X211073428

  View details for PubMedID 35108126

• COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US cohort. PloS one Ward, A., Sarraju, A., Lee, D., Bhasin, K., Gad, S., Beetel, R., Chang, S., Bonafede, M., Rodriguez, F., Dash, R. 2022; 17 (1): e0261786

  Abstract

  Infection with SARS-CoV-2 is typically compared with influenza to contextualize its health risks. SARS-CoV-2 has been linked with coagulation disturbances including arterial thrombosis, leading to considerable interest in antithrombotic therapy for Coronavirus Disease 2019 (COVID-19). However, the independent thromboembolic risk of SARS-CoV-2 infection compared with influenza remains incompletely understood. We evaluated the adjusted risks of thromboembolic events after a diagnosis of COVID-19 compared with influenza in a large retrospective cohort.We used a US-based electronic health record (EHR) dataset linked with insurance claims to identify adults diagnosed with COVID-19 between April 1, 2020 and October 31, 2020. We identified influenza patients diagnosed between October 1, 2018 and April 31, 2019. Primary outcomes [venous composite of pulmonary embolism (PE) and acute deep vein thrombosis (DVT); arterial composite of ischemic stroke and myocardial infarction (MI)] and secondary outcomes were assessed 90 days post-diagnosis. Propensity scores (PS) were calculated using demographic, clinical, and medication variables. PS-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression.There were 417,975 COVID-19 patients (median age 57y, 61% women), and 345,934 influenza patients (median age 47y, 66% women). Compared with influenza, patients with COVID-19 had higher venous thromboembolic risk (HR 1.53, 95% CI 1.38-1.70), but not arterial thromboembolic risk (HR 1.02, 95% CI 0.95-1.10). Secondary analyses demonstrated similar risk for ischemic stroke (HR 1.11, 95% CI 0.98-1.25) and MI (HR 0.93, 95% CI 0.85-1.03) and higher risk for DVT (HR 1.36, 95% CI 1.19-1.56) and PE (HR 1.82, 95% CI 1.57-2.10) in patients with COVID-19.In a large retrospective US cohort, COVID-19 was independently associated with higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared with influenza. These findings may inform crucial knowledge gaps regarding the specific thromboembolic risks of COVID-19.

  View details for DOI 10.1371/journal.pone.0261786

  View details for PubMedID 35020742

• Validation of a pandemic-proof, decentralized cardiovascular trial: scalable design produces rapid recruitment, high engagement and protocol adherence in DeTAP (Decentralized Trial in Afib Patients) Josan, K., Touros, A., Petlura, C., Parameswaran, V., Grewal, U., Senior, M., Viethen, T., Mundl, H., Seninger, C., Luithle, J., Mahaffey, K., Turakhia, M., Dash, R. OXFORD UNIV PRESS. 2021: 3177

  View details for Web of Science ID 000720456903478

• Initial Outcomes of CardioClick, a Telehealth Program for Preventive Cardiac Care: Observational Study. JMIR cardio Kalwani, N. M., Johnson, A. N., Parameswaran, V., Dash, R., Rodriguez, F. 2021; 5 (2): e28246

  Abstract

  BACKGROUND: Telehealth use has increased in specialty clinics, but there is limited evidence on the outcomes of telehealth in primary cardiovascular disease (CVD) prevention.OBJECTIVE: The objective of this study was to evaluate the initial outcomes of CardioClick, a telehealth primary CVD prevention program.METHODS: In 2017, the Stanford South Asian Translational Heart Initiative (a preventive cardiology clinic focused on high-risk South Asian patients) introduced CardioClick, which is a clinical pathway replacing in-person follow-up visits with video visits. We assessed patient engagement and changes in CVD risk factors in CardioClick patients and in a historical in-person cohort from the same clinic.RESULTS: In this study, 118 CardioClick patients and 441 patients who received in-person care were included. CardioClick patients were more likely to complete the clinic's CVD prevention program (76/118, 64.4% vs 173/441, 39.2%, respectively; P<.001) and they did so in lesser time (mean, 250 days vs 307 days, respectively; P<.001) than the patients in the historical in-person cohort. Patients who completed the CardioClick program achieved reductions in CVD risk factors, including blood pressure, lipid concentrations, and BMI, which matched or exceeded those observed in the historical in-person cohort.CONCLUSIONS: Telehealth can be used to deliver care effectively in a preventive cardiology clinic setting and may result in increased patient engagement. Further studies on telehealth outcomes are needed to determine the optimal role of virtual care models across diverse preventive medicine clinics.

  View details for DOI 10.2196/28246

  View details for PubMedID 34499037

• Ferumoxytol-enhanced cardiovascular magnetic resonance detection of early stage acute myocarditis. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance Tada, Y., Tachibana, A., Heidary, S., Yang, P. C., McConnell, M. V., Dash, R. 2019; 21 (1): 77

  Abstract

  BACKGROUND: The diagnostic utility of cardiovascular magnetic resonance (CMR) is limited during the early stages of myocarditis. This study examined whether ferumoxytol-enhanced CMR (FE-CMR) could detect an earlier stage of acute myocarditis compared to gadolinium-enhanced CMR.METHODS: Lewis rats were induced to develop autoimmune myocarditis. CMR (3T, GE Signa) was performed at the early- (day 14, n=7) and the peak-phase (day 21, n=8) of myocardial inflammation. FE-CMR was evaluated as % myocardial dephasing signal loss on gradient echo images at 6 and 24h (6h- & 24h-FE-CMR) following the administration of ferumoxytol (300mumolFe/kg). Pre- and post-contrast T2* mapping was also performed. Early (EGE) and late (LGE) gadolinium enhancement was obtained after the administration of gadolinium-DTPA (0.5mmol/kg) on day 14 and 21. Healthy rats were used as control (n=6).RESULTS: Left ventricular ejection fraction (LVEF) was preserved at day 14 with inflammatory cells but no fibrosis seen on histology. EGE and LGE at day 14 both showed limited myocardial enhancement (EGE: 11.7±15.5%; LGE: 8.7±8.7%; both p=ns vs. controls). In contrast, 6h-FE-CMR detected extensive myocardial signal loss (33.2±15.0%, p=0.02 vs. EGE and p<0.01 vs. LGE). At day 21, LVEF became significantly decreased (47.4±16.4% vs control: 66.2±6.1%, p<0.01) with now extensive myocardial involvement detected on EGE, LGE, and 6h-FE-CMR (41.6±18.2% of LV). T2* mapping also detected myocardial uptake of ferumoxytol both at day 14 (6h R2*=299±112s-1vs control: 125±26s-1, p<0.01) and day 21 (564±562s-1, p<0.01 vs control). Notably, the myocardium at peak-phase myocarditis also showed significantly higher pre-contrast T2* (27±5ms vs control: 16±1ms, p<0.001), and the extent of myocardial necrosis had a strong positive correlation with T2* (r=0.86, p<0.001).CONCLUSIONS: FE-CMR acquired at 6h enhance detection of early stages of myocarditis before development of necrosis or fibrosis, which could potentially enable appropriate therapeutic intervention.

  View details for DOI 10.1186/s12968-019-0587-7

  View details for PubMedID 31842900

• Efficacy of a Telehealth Preventive Cardiology Lifestyle Intervention Program to Treat High-Risk South Asians Parameswaran, V., Josan, K., Khandelwal, A., Abbasi, F., Dash, R. AMER DIABETES ASSOC. 2019

  View details for DOI 10.2337/db19-885-P

  View details for Web of Science ID 000501366902250

• Myocardial viability of the peri-infarct region measured by T1 mapping post manganese-enhanced MRI correlates with LV dysfunction. International journal of cardiology Tada, Y., Heidary, S., Tachibana, A., Zaman, J., Neofytou, E., Dash, R., Wu, J. C., Yang, P. C. 2019

  Abstract

  BACKGROUND: Manganese-enhanced MRI (MEMRI) detects viable cardiomyocytes based on the intracellular manganese uptake via L-type calcium-channels. This study aimed to quantify myocardial viability based on manganese uptake by viable myocardium in the infarct core (IC), peri-infarct region (PIR) and remote myocardium (RM) using T1 mapping before and after MEMRI and assess their association with cardiac function and arrhythmogenesis.METHODS: Fifteen female swine had a 60-minute balloon ischemia-reperfusion injury in the LAD. MRI (Signa 3T, GE Healthcare) and electrophysiological study (EPS) were performed 4 weeks later. MEMRI and delayed gadolinium-enhanced MRI (DEMRI) were acquired on LV short axis. The DEMRI positive total infarct area was subdivided into the regions of MEMRI-negative non-viable IC and MEMRI-positive viable PIR. T1 mapping was performed to evaluate native T1, post-MEMRI T1, and delta R1 (R1post-R1pre, where R1 equals 1/T1) of each territory. Their correlation with LV function and EPS data was assessed.RESULTS: PIR was characterized by intermediate native T1 (1530.5 ± 75.2 ms) compared to IC (1634.7 ± 88.4 ms, p = 0.001) and RM (1406.4 ± 37.9 ms, p < 0.0001). Lower post-MEMRI T1 of PIR (1136.3 ± 99.6 ms) than IC (1262.6 ± 126.8 ms, p = 0.005) and higher delta R1 (0.23 ± 0.08 s-1) of PIR than IC (0.18 ± 0.09 s-1, p = 0.04) indicated higher myocardial manganese uptake of PIR compared to IC. Post-MEMRI T1 (r = -0.57, p = 0.02) and delta R1 (r = 0.51, p = 0.04) of PIR correlated significantly with LVEF.CONCLUSIONS: PIR is characterized by higher manganese uptake compared to the infarct core. In the subacute phase post-IR, PIR viability measured by post-MEMRI T1 correlates with cardiac function.

  View details for PubMedID 30739802

• Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging. PloS one Miller, R. J., Heidary, S. n., Pavlovic, A. n., Schlachter, A. n., Dash, R. n., Fleischmann, D. n., Ashley, E. A., Wheeler, M. T., Yang, P. C. 2019; 14 (6): e0217612

  Abstract

  HCM is the most common inherited cardiomyopathy. Historically, there has been poor correlation between genotype and phenotype. However, CMR has the potential to more accurately assess disease phenotype. We characterized phenotype with CMR in a cohort of patients with confirmed HCM and high prevalence of genetic testing.Patients with a diagnosis of HCM, who had undergone contrast-enhanced CMR were identified. Left ventricular mass index (LVMI) and volumes were measured from steady-state free precession sequences. Late gadolinium enhancement (LGE) was quantified using the full width, half maximum method. All patients were prospectively followed for the development of septal reduction therapy, arrhythmia or death.We included 273 patients, mean age 51.2 ± 15.5, 62.9% male. Of those patients 202 (74.0%) underwent genetic testing with 90 pathogenic, likely pathogenic, or rare variants and 13 variants of uncertain significance identified. Median follow-up was 1138 days. Mean LVMI was 82.7 ± 30.6 and 145 patients had late gadolinium enhancement (LGE). Patients with beta-myosin heavy chain (MYH7) mutations had higher LV ejection fraction (68.8 vs 59.1, p<0.001) than those with cardiac myosin binding protein C (MYBPC3) mutations. Patients with MYBPC3 mutations were more likely to have LVEF < 55% (29.7% vs 4.9%, p = 0.005) or receive a defibrillator than those with MYH7 mutations (54.1% vs 26.8%, p = 0.020).We found that patients with MYBPC3 mutations were more likely to have impaired ventricular function and may be more prone to arrhythmic events. Larger studies using CMR phenotyping may be capable of identifying additional characteristics associated with less frequent genetic causes of HCM.

  View details for DOI 10.1371/journal.pone.0217612

  View details for PubMedID 31199839

• CardioClick an Innovative Telehealth Approach to Lifestyle Intervention in High Risk South Asians Parameswaran, V., Josan, K., Winterbottom, J., Shearer, J., Khandelwal, A., Nallamshetty, S., Dash, R., Rodriguez, F. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for DOI 10.1161/circ.139.suppl_1.P337

  View details for Web of Science ID 000478079000280

• Index of Microcirculatory Resistance and Infarct Size. JACC. Cardiovascular imaging Fearon, W. F., Dash, R. 2018

  View details for PubMedID 29680353

• Dose-Dependent Cardioprotection of Moderate (32°C) Versus Mild (35°C) Therapeutic Hypothermia in Porcine Acute Myocardial Infarction. JACC. Cardiovascular interventions Dash, R. n., Mitsutake, Y. n., Pyun, W. B., Dawoud, F. n., Lyons, J. n., Tachibana, A. n., Yahagi, K. n., Matsuura, Y. n., Kolodgie, F. D., Virmani, R. n., McConnell, M. V., Illindala, U. n., Ikeno, F. n., Yeung, A. n. 2018; 11 (2): 195–205

  Abstract

  The study investigated whether a dose response exists between myocardial salvage and the depth of therapeutic hypothermia.Cardiac protection from mild hypothermia during acute myocardial infarction (AMI) has yielded equivocal clinical trial results. Rapid, deeper hypothermia may improve myocardial salvage.Swine (n = 24) undergoing AMI were assigned to 3 reperfusion groups: normothermia (38°C) and mild (35°C) and moderate (32°C) hypothermia. One-hour anterior myocardial ischemia was followed by rapid endovascular cooling to target reperfusion temperature. Cooling began 30 min before reperfusion. Target temperature was reached before reperfusion and was maintained for 60 min. Infarct size (IS) was assessed on day 6 using cardiac magnetic resonance, triphenyl tetrazolium chloride, and histopathology.Triphenyl tetrazolium chloride area at risk (AAR) was equivalent in all groups (p = 0.2), but 32°C exhibited 77% and 91% reductions in IS size per AAR compared with 35°C and 38°C, respectively (AAR: 38°C, 45 ± 12%; 35°C, 17 ± 10%; 32°C, 4 ± 4%; p < 0.001) and comparable reductions per LV mass (LV mass: 38°C, 14 ± 5%; 35°C, 5 ± 3%; 32°C 1 ± 1%; p < 0.001). Importantly, 32°C showed a lower IS AAR (p = 0.013) and increased immunohistochemical granulation tissue versus 35°C, indicating higher tissue salvage. Delayed-enhancement cardiac magnetic resonance IS LV also showed marked reduction at 32°C (38°C: 10 ± 4%, p < 0.001; 35°C: 8 ± 3%; 32°C: 3 ± 2%, p < 0.001). Cardiac output on day 6 was only preserved at 32°C (reduction in cardiac output: 38°C, -29 ± 19%, p = 0.041; 35°C: -17 ± 33%; 32°C: -1 ± 28%, p = 0.041). Using linear regression, the predicted IS reduction was 6.7% (AAR) and 2.1% (LV) per every 1°C reperfusion temperature decrease.Moderate (32°C) therapeutic hypothermia demonstrated superior and near-complete cardioprotection compared with 35°C and control, warranting further investigation into clinical applications.

  View details for PubMedID 29348013

• An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice PLOS ONE Montgomery, M. D., Chan, T., Swigart, P. M., Myagmar, B., Dash, R., Simpson, P. C. 2017; 12 (1)

  Abstract

  Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35-40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies.

  View details for DOI 10.1371/journal.pone.0168409

  View details for Web of Science ID 000391949500011

  View details for PubMedID 28081170

  View details for PubMedCentralID PMC5231318

• Manganese-Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri-Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia-Reperfusion Model. Journal of the American Heart Association Dash, R., Kim, P. J., Matsuura, Y., Ikeno, F., Metzler, S., Huang, N. F., Lyons, J. K., Nguyen, P. K., Ge, X., Foo, C. W., McConnell, M. V., Wu, J. C., Yeung, A. C., Harnish, P., Yang, P. C. 2015; 4 (7)

  Abstract

  The exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri-infarct region (PIR) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese-enhanced magnetic resonance imaging [MEMRI]), myocardial scar (delayed gadolinium enhancement MRI), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts.Twelve adult swine underwent ischemia-reperfusion injury. Digital subtraction of MEMRI-negative myocardium (intrainfarct region) from delayed gadolinium enhancement MRI-positive myocardium (PIR and intrainfarct region) clearly delineated the PIR in which the MEMRI-positive signal reflected PIR viability. Human amniotic mesenchymal stem cells (hAMSCs) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine PIR. Immediately following hAMSC delivery, MEMRI demonstrated an increased PIR viability signal compared with control. Direct PIR viability remained higher in hAMSC-treated hearts for >6 weeks. Increased PIR viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and hAMSC engraftment, as confirmed by immunocytochemistry. Increased MEMRI and positron emission tomography reporter gene signal in the intrainfarct region and the PIR correlated with sustained functional augmentation (global and regional) within the hAMSC group (mean change, left ventricular ejection fraction: hAMSC 85±60%, control 8±10%; P<0.05) and reduced chamber dilatation (left ventricular end-diastole volume increase: hAMSC 24±8%, control 110±30%; P<0.05).The positron emission tomography reporter gene signal of hAMSC engraftment correlates with the improved MEMRI signal in the PIR. The increased MEMRI signal represents PIR viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real-time method of tracking PIR viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells.

  View details for DOI 10.1161/JAHA.115.002044

  View details for PubMedID 26215972

• Synthesis of an in vivo MRI-detectable apoptosis probe. Journal of visualized experiments : JoVE Lam, J., Simpson, P. C., Yang, P. C., Dash, R. 2012

  Abstract

  Cellular apoptosis is a prominent feature of many diseases, and this programmed cell death typically occurs before clinical manifestations of disease are evident. A means to detect apoptosis in its earliest, reversible stages would afford a pre-clinical 'window' during which preventive or therapeutic measures could be taken to protect the heart from permanent damage. We present herein a simple and robust method to conjugate human Annexin V (ANX), which avidly binds to cells in the earliest, reversible stages of apoptosis, to superparamagnetic iron oxide (SPIO) nanoparticles, which serve as an MRI-detectable contrast agent. The conjugation method begins with an oxidation of the SPIO nanoparticles, which oxidizes carboxyl groups on the polysaccharide shell of SPIO. Purified ANX protein is then added in the setting of a sodium borate solution to facilitate covalent interaction of ANX with SPIO in a reducing buffer. A final reduction step with sodium borohydride is performed to complete the reduction, and then the reaction is quenched. Unconjugated ANX is removed from the mix by microcentrifuge filtration. The size and purity of the ANX-SPIO product is verified by dynamic light scattering (DLS). This method does not require addition to, or modification of, the polysaccharide SPIO shell, as opposed to cross-linked iron oxide particle conjugation methods or biotin-labeled nanoparticles. As a result, this method represents a simple, robust approach that may be extended to conjugation of other proteins of interest.

  View details for DOI 10.3791/3775

  View details for PubMedID 22871963

• A Molecular MRI Probe to Detect Treatment of Cardiac Apoptosis In Vivo MAGNETIC RESONANCE IN MEDICINE Dash, R., Chung, J., Chan, T., Yamada, M., Barral, J., Nishimura, D., Yang, P. C., Simpson, P. C. 2011; 66 (4): 1152-1162

  Abstract

  Cell death by apoptosis is critical in myocardial diseases, and noninvasive detection of early, reversible apoptosis might be useful clinically. Exogenous Annexin-V (ANX) protein binds membrane phosphatidylserine, which is externalized in early apoptosis. A molecular MRI probe was constructed with superparamagnetic iron oxide (SPIO) conjugated to recombinant human ANX (ANX-SPIO). Apoptosis was induced with doxorubicin, a cardiotoxic cancer drug, in culture in neonatal rat ventricular myocytes, cardiac fibroblasts, and mesenchymal stem cells, and in vivo in the mouse heart. ANX-SPIO was validated using T2*-weighted 3T MRI. ANX-SPIO produced T2* signal loss, reflecting iron content, that correlated highly with independent apoptosis markers; bound with high affinity to apoptotic myocytes by competition assay (Ki 69 nM); detected apoptosis in culture much earlier than did TUNEL stain; and revealed fibroblast resistance to apoptosis. With apoptosis in vivo, ANX-SPIO produced diffuse myocardial T2* signal loss that correlated with increased iron stain and caspase activity. Treatment with an alpha-1-adrenergic agonist in vivo reversed apoptosis and eliminated the ANX-SPIO MRI signal. It is concluded that cardiac MRI of ANX-SPIO detects early, nonischemic cardiac apoptosis in culture and in vivo, and can identify reversibly injured cardiac cells in diseased hearts, when treatment is still possible.

  View details for DOI 10.1002/mrm.22876

  View details for Web of Science ID 000295356500027

  View details for PubMedID 21360750

  View details for PubMedCentralID PMC3138815

• Dual Manganese-Enhanced and Delayed Gadolinium-Enhanced MRI Detects Myocardial Border Zone Injury in a Pig Ischemia-Reperfusion Model CIRCULATION-CARDIOVASCULAR IMAGING Dash, R., Chung, J., Ikeno, F., Hahn-Windgassen, A., Matsuura, Y., Bennett, M. V., Lyons, J. K., Teramoto, T., Robbins, R. C., McConnell, M. V., Yeung, A. C., Brinton, T. J., Harnish, P. P., Yang, P. C. 2011; 4 (5): 574-582

  Abstract

  Gadolinium (Gd)-based delayed-enhancement MRI (DEMRI) identifies nonviable myocardium but is nonspecific and may overestimate nonviable territory. Manganese (Mn(2+))-enhanced MRI (MEMRI) denotes specific Mn(2+) uptake into viable cardiomyocytes. We performed a dual-contrast myocardial assessment in a porcine ischemia-reperfusion (IR) model to test the hypothesis that combined DEMRI and MEMRI identifies viable infarct border zone (BZ) myocardium in vivo.Sixty-minute left anterior descending coronary artery IR injury was induced in 13 adult swine. Twenty-one days post-IR, 3-T cardiac MRI was performed. MEMRI was obtained after injection of 0.7 mL/kg Mn(2+) contrast agent. DEMRI was then acquired after injection of 0.2 mmol/kg Gd. Left ventricular (LV) mass, infarct, and function were analyzed. Subtraction of MEMRI defect from DEMRI signal identified injured BZ myocardium. Explanted hearts were analyzed by 2,3,5-triphenyltetrazolium chloride stain and tissue electron microscopy to compare infarct, BZ, and remote myocardium. Average LV ejection fraction was reduced (30±7%). MEMRI and DEMRI infarct volumes correlated with 2,3,5-triphenyltetrazolium chloride stain analysis (MEMRI, r=0.78; DEMRI, r=0.75; P<0.004). MEMRI infarct volume percentage was significantly lower than that of DEMRI (14±4% versus 23±4%; P<0.05). BZ MEMRI signal-to-noise ratio (SNR) was intermediate to remote and core infarct SNR (7.5±2.8 versus 13.2±3.4 and 2.9±1.6; P<0.0001), and DEMRI BZ SNR tended to be intermediate to remote and core infarct SNR (8.4±5.4 versus 3.3±0.6 and 14.3±6.6; P>0.05). Tissue electron microscopy analysis exhibited preserved cell structure in BZ cardiomyocytes despite transmural DEMRI enhancement.The dual-contrast MEMRI-DEMRI detects BZ viability within DEMRI infarct zones. This approach may identify injured, at-risk myocardium in ischemic cardiomyopathy.

  View details for DOI 10.1161/CIRCIMAGING.110.960591

  View details for PubMedID 21719779

• Detection of Injured Border Zone Myocardium Using Manganese-Enhanced and Delayed-Enhanced MRI in a Pig Ischemia-Reperfusion Model Dash, R., Chung, J., Hahn-Windgassen, A., Matsuura, Y., Ikeno, F., Lyons, J., Teramoto, T., Yeung, A. C., McConnell, M. V., Brinton, T. J., Harnish, P., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231600841

• Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy CARDIOVASCULAR RESEARCH Dash, R., Schmidt, A. G., Pathak, A., Gerst, M. J., Biniakiewicz, D., Kadambi, V. J., Hoit, B. D., Abraham, W. T., Kranias, E. G. 2003; 57 (3): 704-714

  Abstract

  Exogenous catecholamine exposure has been associated with p38 mitogen-activated protein kinase (MAPK) and cardiac hypertrophy. In this study, we investigated the regulation of p38 MAPK in cardiac remodeling elicited by endogenous adrenergic mechanisms.Transgenic male and female mice with fourfold phospholamban (PLB) overexpression exhibited enhanced circulating norepinephrine (NE), as a physiological compensatory mechanism to attenuate PLB's inhibitory effects. This enhanced noradrenergic state resulted in left ventricular hypertrophy/dilatation and depressed function.Male transgenics exhibited ventricular hypertrophy and mortality at 15 months, concurrent with cardiac p38 MAPK activation. Female transgenics, despite similar contractile dysfunction, displayed a temporal delay in p38 activation, hypertrophy, and mortality (22 months), which was associated with sustained cardiac levels of MAP Kinase Phosphatase-1 (MKP-1), a potent inhibitor of p38. At 22 months, decreases in cardiac MKP-1 were accompanied by increased levels of p38 activation. In vitro studies indicated that preincubation with 17-beta-estradiol induced high MKP-1 levels, which precluded NE-induced p38 activation.These findings suggest that norepinephrine-induced hypertrophy is linked closely with p38 MAP kinase activation, which can be endogenously modulated through estrogen-responsive regulation of MKP-1 expression.

  View details for DOI 10.1016/S0008-6363(02)00772-1

  View details for Web of Science ID 000181791200013

  View details for PubMedID 12618232

• Gender influences on sarcoplasmic reticulum Ca2+-handling in failing human myocardium JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Dash, R., Frank, K. F., Carr, A. N., Moravec, C. S., Kranias, E. G. 2001; 33 (7): 1345-1353

  Abstract

  Gender has recently been implicated as an important modulator of cardiovascular disease. However, it is not known how gender may specifically influence the Ca2+-handling deficits that characterize the depressed cardiac contractility of human heart failure. To elucidate the contributory role of gender to sarcoplasmic reticulum (SR) Ca2+ cycling alterations, the protein levels of SR Ca2+-ATPase (SERCA), phospholamban, and calsequestrin, as well as the site-specific phospholamban phosphorylation status, were quantified in a mixed gender population of failing (n=14) and donor (n=15) myocardia. The apparent affinity (EC50) and the maximal velocity (Vmax) of SR Ca2+-uptake were also determined to lend functional significance to any observed protein alterations. Phospholamban and calsequestrin levels were not altered; however, SERCA protein levels were significantly reduced in failing hearts. Additionally, phospholamban phosphorylation (serine-16 and threonine-17 sites) and myocardial cAMP content were both attenuated. The alterations in SR protein levels were also accompanied by a decreased V(max)and an increased EC50 (diminished apparent affinity) of SR Ca2+-uptake for Ca2+ in failing myocardia. Myocardial protein levels and Ca2+ uptake parameters were then analyzed with respect to gender, which revealed that the decreases in phosphorylated serine-16 were specific to male failing hearts, reflecting increases in the EC50 values of SR Ca2+-uptake for Ca2+, compared to donor males. These findings suggest that although decreased SERCA protein and phospholamban phosphorylation levels contribute to depressed SR Ca2+-uptake and left ventricular function in heart failure, the specific subcellular alterations which underlie these effects may not be uniform with respect to gender.

  View details for DOI 10.1006/jmcc.2001.1394

  View details for Web of Science ID 000171322800006

  View details for PubMedID 11437540

• Interactions between phospholamban and beta-adrenergic drive may lead to cardiomyopathy and early mortality CIRCULATION Dash, R., Kadambi, V. J., Schmidt, A. G., Tepe, N. M., Biniakiewicz, D., Gerst, M. J., Canning, A. M., Abraham, W. T., Hoit, B. D., Liggett, S. B., Lorenz, J. N., Dorn, G. W., Kranias, E. G. 2001; 103 (6): 889-896

  Abstract

  Relieving the inhibition of sarcoplasmic reticular function by phospholamban is a major target of beta-adrenergic stimulation. Chronic beta-adrenergic receptor activity has been suggested to be detrimental, on the basis of transgenic overexpression of the receptor or its signaling effectors. However, it is not known whether physiological levels of sympathetic tone, in the absence of preexisting heart failure, are similarly detrimental.Transgenic mice overexpressing phospholamban at 4-fold normal levels were generated, and at 3 months, they exhibited mildly depressed ventricular contractility without heart failure. As expected, transgenic cardiomyocyte mechanics and calcium kinetics were depressed, but isoproterenol reversed the inhibitory effects of phospholamban on these parameters. In vivo cardiac function was substantially depressed by propranolol administration, suggesting enhanced sympathetic tone. Indeed, plasma norepinephrine levels and the phosphorylation status of phospholamban were elevated, reflecting increased adrenergic drive in transgenic hearts. On aging, the chronic enhancement of adrenergic tone was associated with a desensitization of adenylyl cyclase (which intensified the inhibitory effects of phospholamban), the development of overt heart failure, and a premature mortality.The unique interaction between phospholamban and increased adrenergic drive, elucidated herein, provides the first evidence that compensatory increases in catecholamine stimulation can, even in the absence of preexisting heart failure, be a primary causative factor in the development of cardiomyopathy and early mortality.

  View details for Web of Science ID 000167561900030

  View details for PubMedID 11171800

• Drivers of variation in telemedicine use during the COVID-19 pandemic: The experience of a large academic cardiovascular practice. Journal of telemedicine and telecare Koos, H., Parameswaran, V., Claire, S., Chen, C., Kalwani, N., Osmanlliu, E., Qureshi, L., Dash, R., Scheinker, D., Rodriguez, F. 2022: 1357633X221130288

  Abstract

  BACKGROUND: COVID-19 spurred rapid adoption and expansion of telemedicine. We investigated the factors driving visit modality (telemedicine vs. in-person) for outpatient visits at a large cardiovascular center.METHODS: We used electronic health record data from March 2020 to February 2021 from four cardiology subspecialties (general cardiology, electrophysiology, heart failure, and interventional cardiology) at a large academic health system in Northern California. There were 21,912 new and return visits with 69% delivered by telemedicine. We used hierarchical logistic regression and cross-validation methods to estimate the variation in visit modality explained by patient, clinician, and visit factors as measured by the mean area under the curve.RESULTS: Across all subspecialties, the clinician seen was the strongest predictor of telemedicine usage, while primary visit diagnosis was the next most predictive. In general cardiology, the model based on clinician seen had a mean area under the curve of 0.83, the model based on the primary diagnosis had a mean area under the curve of 0.69, and the model based on all patient characteristics combined had a mean area under the curve of 0.56. There was significant variation in telemedicine use across clinicians within each subspecialty, even for visits with the same primary visit diagnosis.CONCLUSION: Individual clinician practice patterns had the largest influence on visit modality across subspecialties in a large cardiovascular medicine practice, while primary diagnosis was less predictive, and patient characteristics even less so. Cardiovascular clinics should reduce variability in visit modality selection through standardized processes that integrate clinical factors and patient preference.

  View details for DOI 10.1177/1357633X221130288

  View details for PubMedID 36214200

• Real-World Diagnosis and Treatment of Diabetic Kidney Disease. Advances in therapy Rodriguez, F., Lee, D. J., Gad, S. S., Santos, M. P., Beetel, R. J., Vasey, J., Bailey, R. A., Patel, A., Blais, J., Weir, M. R., Dash, R. 2021

  Abstract

  INTRODUCTION: People with type2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD) have increased morbidity and mortality risk. Angiotensin-converting enzyme inhibitors (ACEi) or angiotensinII receptor blockers (ARB) are recommended to slow kidney function decline in DKD. This representative, real-world data analysis of patients with T2DM was performed to detect onset of DKD and determine methods and timing of DKD diagnosis and time to initiation of ACEi/ARB therapy.METHODS: Patients diagnosed with T2DM before January1, 2016 who developed DKD between January1, 2017 and June30, 2019 were identified from a longitudinal ambulatory electronic health record (EHR) dataset (Veradigm Inc). Each record was analyzed using the CLinical INTelligence engine (CLINT, HealthPals, Inc.) to identify delays and gaps in diagnosing DKD. DKD was diagnosed through two reduced estimated glomerular filtration rate (eGFR; <60mL/min/1.73m2) measurements at least 90days apart, a single elevated urine albumin-to-creatinine ratio (UACR; >30mg/g) measurement, or ICD-9/10 diagnosis codes for DKD and/or albuminuria. Time to diagnose (TTD), time to treat (TTT), and diagnosis to treatment time were assessed.RESULTS: Of 6,499,409 patients with T2DM before January 2016, 245,978 developed DKD between January1, 2017 and June30, 2019. In this DKD cohort, ca. 50% were first identified through EHR diagnosis and ca. 50% by UACR or eGFR lab-based diagnosis. In patients who had UACR/eGFR assessed, more than 90% exhibited DKD-level results on the first diagnostic test. Average TTD after eGFR labs was 2years; average TTT with ACEi/ARB was 6-9months after DKD lab evidence. The majority of patients who developed DKD received ACEi/ARB therapy 6-7months after diagnosis.CONCLUSION: In a contemporary, large national cohort of patients with T2DM, progression to DKD was common but likely underrepresented. The low rate of DKD-screening labs, along with sizable delays in diagnosis of DKD and initiation of ACEi/ARB therapy, indicates that many patients who progress to DKD are not being properly treated.

  View details for DOI 10.1007/s12325-021-01777-9

  View details for PubMedID 34254257

• Application of the Quadruple Aim to evaluate the operational impact of a telemedicine program. Healthcare (Amsterdam, Netherlands) Kalwani, N. M., Wang, K. M., Johnson, A. N., Deb, J. D., Gold, T., Maddukuri, A. K., Savage, E. G., Parameswaran, V., Dash, R., Scheinker, D., Rodriguez, F. 2021; 9 (4): 100593

  Abstract

  In response to the COVID-19 pandemic, telemedicine utilization has increased dramatically, yet most institutions lack a standardized approach to determine how much to invest in these programs.We used the Quadruple Aim to evaluate the operational impact of CardioClick, a program replacing in-person follow-up visits with video visits in a preventive cardiology clinic. We examined data for 134 patients enrolled in CardioClick with 181 video follow-up visits and 276 patients enrolled in the clinic's traditional prevention program with 694 in-person follow-up visits.Patients in CardioClick and the cohort receiving in-person care were similar in terms of age (43 vs 45 years), gender balance (74% vs 79% male), and baseline clinical characteristics. Video follow-up visits were shorter than in-person visits in terms of clinician time (median 22 vs 30 min) and total clinic time (median 22 vs 68 min). Video visits were more likely to end on time than in-person visits (71 vs 11%, p < .001). Physicians more often completed video visit documentation on the day of the visit (56 vs 42%, p = .002).Implementation of video follow-up visits in a preventive cardiology clinic was associated with operational improvements in the areas of efficiency, patient experience, and clinician experience. These benefits in three domains of the Quadruple Aim justify expanded use of telemedicine at our institution.The Quadruple Aim provides a framework to evaluate telemedicine programs recently implemented in many health systems.Level III (retrospective comparative study).

  View details for DOI 10.1016/j.hjdsi.2021.100593

  View details for PubMedID 34749227

• Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement. The New England journal of medicine Makkar, R. R., Thourani, V. H., Mack, M. J., Kodali, S. K., Kapadia, S., Webb, J. G., Yoon, S., Trento, A., Svensson, L. G., Herrmann, H. C., Szeto, W. Y., Miller, D. C., Satler, L., Cohen, D. J., Dewey, T. M., Babaliaros, V., Williams, M. R., Kereiakes, D. J., Zajarias, A., Greason, K. L., Whisenant, B. K., Hodson, R. W., Brown, D. L., Fearon, W. F., Russo, M. J., Pibarot, P., Hahn, R. T., Jaber, W. A., Rogers, E., Xu, K., Wheeler, J., Alu, M. C., Smith, C. R., Leon, M. B., PARTNER 2 Investigators 2020; 382 (9)

  Abstract

  BACKGROUND: There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk.METHODS: We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.3% and 23.7%, respectively) and were randomly assigned to undergo either TAVR or surgical replacement. Clinical, echocardiographic, and health-status outcomes were followed for 5 years. The primary end point was death from any cause or disabling stroke.RESULTS: At 5 years, there was no significant difference in the incidence of death from any cause or disabling stroke between the TAVR group and the surgery group (47.9% and 43.4%, respectively; hazard ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; P=0.21). Results were similar for the transfemoral-access cohort (44.5% and 42.0%, respectively; hazard ratio, 1.02; 95% CI, 0.87 to 1.20), but the incidence of death or disabling stroke was higher after TAVR than after surgery in the transthoracic-access cohort (59.3% vs. 48.3%; hazard ratio, 1.32; 95% CI, 1.02 to 1.71). At 5 years, more patients in the TAVR group than in the surgery group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%). Repeat hospitalizations were more frequent after TAVR than after surgery (33.3% vs. 25.2%), as were aortic-valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar for TAVR and surgery.CONCLUSIONS: Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

  View details for DOI 10.1056/NEJMoa1910555

  View details for PubMedID 31995682

• Index of Microcirculatory Resistance and Infarct Size JACC-CARDIOVASCULAR IMAGING Fearon, W. F., Dash, R. 2019; 12 (5): 849–51

  View details for DOI 10.1016/j.jcmg.2018.04.004

  View details for Web of Science ID 000467057900012

• INSULIN RESISTANCE ASSOCIATES WITH ADVERSE CARDIAC REMODELING IN THE ABSENCE OF HYPERTENSION IN YOUNG SOUTH ASIANS Bose, R., Arora, M., Abbasi, F., Roy, E., Nallamshetty, S., Khandelwal, A., Ranade, P., Dash, R. ELSEVIER SCIENCE INC. 2017: 1871

  View details for Web of Science ID 000397342302593

• Therapeutic Hypothermia in Postcardiac Arrest. Therapeutic hypothermia and temperature management Polderman, K. H., Dash, R., Nichol, G., Deye, N. 2017; 7 (1): 2-7

  View details for DOI 10.1089/ther.2016.29023.kjp

  View details for PubMedID 28106521

• Apelin-13 infusion salvages the peri-infarct region to preserve cardiac function after severe myocardial injury INTERNATIONAL JOURNAL OF CARDIOLOGY Chung, W., Cho, A., Byun, K., Moon, J., Ge, X., Seo, H., Moon, E., Dash, R., Yang, P. C. 2016; 222: 361-367

  Abstract

  Apelin-13 (A13) regulates cardiac homeostasis. However, the effects and mechanism of A13 infusion after an acute myocardial injury (AMI) have not been elucidated. This study assesses the restorative effects and mechanism of A13 on the peri-infarct region in murine AMI model.51 FVB/N mice (12weeks, 30g) underwent AMI. A week following injury, continuous micro-pump infusion of A13 (0.5μg/g/day) and saline was initiated for 4-week duration. Dual contrast MRI was conducted on weeks 1, 2, 3, and 5, consisting of delayed-enhanced and manganese-enhanced MRI. Four mice in each group were followed for an extended period of 4weeks without further infusion and underwent MRI scans on weeks 7 and 9.A13 infusion demonstrated preserved LVEF compared to saline from weeks 1 to 4 (21.9±3.2% to 23.1±1.7%* vs. 23.5±1.7% to 16.9±2.8%, *p=0.02), which persisted up to 9weeks post-MI (+1.4%* vs. -9.4%, *p=0.03). Mechanistically, dual contrast MRI demonstrated significant decrease in the peri-infarct and scar % volume in A13 group from weeks 1 to 4 (15.1 to 7.4% and 34.3 to 25.1%, p=0.02, respectively). This was corroborated by significant increase in 5-ethynyl-2'-deoxyuridine (EdU(+)) cells by A13 vs. saline groups in the peri-infarct region (16.5±3.1% vs. 8.1±1.6%; p=0.04), suggesting active cell mitosis. Finally, significantly enhanced mobilization of CD34(+) cells in the peripheral blood and up-regulation of APJ, fibrotic, and apoptotic genes in the peri-infarct region were found.A13 preserves cardiac performance by salvaging the peri-infarct region and may contribute to permanent restoration of the severely injured myocardium.

  View details for DOI 10.1016/j.ijcard.2016.07.263

  View details for PubMedID 27500765

• Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging. Radiology Parashurama, N., Ahn, B., Ziv, K., Ito, K., Paulmurugan, R., Willmann, J. K., Chung, J., Ikeno, F., Swanson, J. C., Merk, D. R., Lyons, J. K., Yerushalmi, D., Teramoto, T., Kosuge, H., Dao, C. N., Ray, P., Patel, M., Chang, Y., Mahmoudi, M., Cohen, J. E., Goldstone, A. B., Habte, F., Bhaumik, S., Yaghoubi, S., Robbins, R. C., Dash, R., Yang, P. C., Brinton, T. J., Yock, P. G., McConnell, M. V., Gambhir, S. S. 2016; 280 (3): 826-836

  Abstract

  Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2016151150

  View details for PubMedID 27332865

• Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and Optical in Vivo Imaging of Bone Marrow Stromal Cells after Myocardial Infarction. Radiology Parashurama, N., Ahn, B., Ziv, K., Ito, K., Paulmurugan, R., Willmann, J. K., Chung, J., Ikeno, F., Swanson, J. C., Merk, D. R., Lyons, J. K., Yerushalmi, D., Teramoto, T., Kosuge, H., Dao, C. N., Ray, P., Patel, M., Chang, Y., Mahmoudi, M., Cohen, J. E., Goldstone, A. B., Habte, F., Bhaumik, S., Yaghoubi, S., Robbins, R. C., Dash, R., Yang, P. C., Brinton, T. J., Yock, P. G., McConnell, M. V., Gambhir, S. S. 2016; 280 (3): 815-825

  Abstract

  Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2016140049

  View details for PubMedID 27308957

• Aligned nanofibrillar collagen scaffolds - Guiding lymphangiogenesis for treatment of acquired lymphedema. Biomaterials Hadamitzky, C., Zaitseva, T. S., Bazalova-Carter, M., Paukshto, M. V., Hou, L., Strassberg, Z., Ferguson, J., Matsuura, Y., Dash, R., Yang, P. C., Kretchetov, S., Vogt, P. M., Rockson, S. G., Cooke, J. P., Huang, N. F. 2016; 102: 259-267

  Abstract

  Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.

  View details for DOI 10.1016/j.biomaterials.2016.05.040

  View details for PubMedID 27348849

• Magnetic Resonance Imaging and Positron Emission Tomography Approaches to Imaging Vascular and Cardiac Inflammation CIRCULATION JOURNAL Amsallem, M., Saito, T., Tada, Y., Dash, R., McConnell, M. V. 2016; 80 (6): 1269-1277

  Abstract

  Inflammation plays a significant role in a wide range of cardiovascular diseases (CVDs). The numerous implications of inflammation in all steps of CVDs, including initiation, progression and complications, have prompted the emergence of noninvasive imaging modalities as diagnostic, prognostic and monitoring tools. In this review, we first synthesize the existing evidence on the role of inflammation in vascular and cardiac diseases, in order to identify the main targets used in noninvasive imaging. We chose to focus on positron emission tomographic (PET) and magnetic resonance imaging (MRI) studies, which offer the greatest potential of translation and clinical application. We detail the main preclinical and clinical studies in the following CVDs: coronary and vascular atherosclerosis, abdominal aortic aneurysms, myocardial infarction, myocarditis, and acute heart transplant rejection. We highlight the potential complementary roles of these imaging modalities, which are currently being studied in the emerging technology of PET/MRI. Finally, we provide a perspective on innovations and future applications of noninvasive imaging of cardiovascular inflammation. (Circ J 2016; 80: 1269-1277).

  View details for DOI 10.1253/circj.CJ-16-0224

  View details for PubMedID 27151335

• Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients NEW ENGLAND JOURNAL OF MEDICINE Leon, M. B., Smith, C. R., Mack, M. J., Makkar, R. R., Svensson, L. G., Kodali, S. K., Thourani, V. H., Tuzcu, E. M., Miller, D. C., Herrmann, H. C., Doshi, D., Cohen, D. J., Pichard, A. D., Kapadia, S., Dewey, T., Babaliaros, V., Szeto, W. Y., Williams, M. R., Kereiakes, D., Zajarias, A., Greason, K. L., Whisenant, B. K., Hodson, R. W., Moses, J. W., Trento, A., Brown, D. L., Fearon, W. F., Pibarot, P., Hahn, R. T., Jaber, W. A., Anderson, W. N., Alu, M. C., Webb, J. G. 2016; 374 (17): 1609-1620

  Abstract

  Previous trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients.We randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort.The rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan-Meier event rates were 19.3% in the TAVR group and 21.1% in the surgery group (hazard ratio in the TAVR group, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoral-access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic-access cohort, outcomes were similar in the two groups. TAVR resulted in larger aortic-valve areas than did surgery and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation.In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

  View details for DOI 10.1056/NEJMoa1514616

  View details for PubMedID 27040324

• Telmisartan in the diabetic murine model of acute myocardial infarction: dual contrast manganese-enhanced and delayed enhancement MRI evaluation of the peri-infarct region. Cardiovascular diabetology Toma, I., Kim, P. J., Dash, R., McConnell, M. V., Nishimura, D., Harnish, P., Yang, P. C. 2016; 15 (1): 24-?

  Abstract

  A novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region. Dual contrast MEMRI-DEMRI enables comprehensive evaluation of telmisartan to salvage the peri-infarct injury to elucidate the underlying mechanism of restoring the ischemic cardiomyopathy in the diabetic mouse model.Dual contrast MEMRI-DEMRI was performed on weeks 1, 2, and 4 following initiation of telmisartan treatment in 24 left anterior descendent artery ligated diabetic mice. The MRI images were analyzed for core infarct, peri-infarct, left ventricular end-diastolic, end-systolic volumes, and the left ventricular ejection fraction (LVEF). Transmission electron microscopy (TEM) and real-time PCR were used for ex vivo analysis of the myocardium. Telmisartan vs. control groups demonstrated significantly improved LVEF at weeks 1, 2, and 4, respectively (33 ± 7 %*** vs. 19 ± 5 %, 29 ± 3 %*** vs. 22 ± 4 %, and 31 ± 2 %*** vs 18 ± 6 %, ***p < 0.001). The control group demonstrated significant differences in the scar volume measured by MEMRI and DEMRI, demonstrating peri-infarct injury. Telmisartan group significantly salvaged the peri-infarct injury. The myocardial effects were validated by TEM, which confirmed the presence of the injured but viable cardiomyocyte morphology in the peri-infarct region and by flow cytometry of venous blood, which demonstrated significantly increased circulating endothelial progenitor cells (EPCs).The improved cardiac function in ischemic cardiomyopathy of diabetic mice by telmisartan is attributed to the attenuation of the peri-infarct injury by the angiogenic effects of EPCs to salvage the injured cardiomyocytes. Dual-contrast MEMRI-DEMRI technique tracked the therapeutic effects of telmisartan on the injured myocardium longitudinally.

  View details for DOI 10.1186/s12933-016-0348-y

  View details for PubMedID 26846539

• Comprehensive Characterization Of Insulin Resistance And Its Association With Ventricular Function In Pulmonary Arterial Hypertension Wells, R. E., Cuttica, M., Dash, R., Abbasi, F., Van de Veerdonk, M., Preston, I. R., Hemnes, A. R., Sweatt, A. J., Gomberg-Maitland, M., Zamanian, R. T. AMER THORACIC SOC. 2016

  View details for Web of Science ID 000390749606233

• Endovascular hypothermia treatment dose-modulates cardioprotection in favor of 32 degrees C target temperature before reperfusion in porcine myocardial infarction Mitsutake, Y., Dash, R., Ikeno, F., Pyun, W., Lyons, J., Dawoud, F., Illindala, U., Yeung, A. ELSEVIER SCIENCE INC. 2015: B94

  View details for DOI 10.1016/j.jacc.2015.08.924

  View details for Web of Science ID 000363329000204

• Rapid endovascular moderate hypothermia before reperfusion provides more cardioprotection than mild hypothermia in a porcine model of myocardial infarction Dash, R., Dawoud, F., Ikeno, F., Tachibana, A., Lyons, J., Mitsutake, Y., Pyun, W. B., McConnell, M., Illindala, U., Yeung, A. OXFORD UNIV PRESS. 2015: 353

  View details for Web of Science ID 000361205103055

• Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Spiekerkoetter, E., Sung, Y. K., Sudheendra, D., Bill, M., Aldred, M. A., van de Veerdonk, M. C., Vonk Noordegraaf, A., Long-Boyle, J., Dash, R., Yang, P. C., Lawrie, A., Swift, A. J., Rabinovitch, M., Zamanian, R. T. 2015; 192 (2): 254-257

  View details for DOI 10.1164/rccm.201411-2061LE

  View details for PubMedID 26177174

• INCREASED MYOCARDIAL VIABILITY AND FUNCTION MEASURED BY MANGANESE-ENHANCED MRI (MEMRI) DEMONSTRATE MYOCARDIAL REGENERATION BY HUMAN PLURIPOTENT STEM CELL DERIVED CARDIOMYOCYTES (HPCMS) Tachibana, A., Rulifson, E., Matsuura, Y., Thakker, R., Wang, M., Wu, J., Dash, R., Yang, P. ELSEVIER SCIENCE INC. 2015: A2147

  View details for DOI 10.1016/S0735-1097(15)62147-7

  View details for Web of Science ID 000375328802469

• THERAPEUTIC HYPOTHERMIA DOSE RESPONSE ON INFARCT SIZE IN ACUTE MYOCARDIAL INFARCTION USING ENDOVASCULAR COOLING AND REWARMING Mitsutake, Y., Pyun, W., Dash, R., Tachibana, A., Matsuura, Y., Green, A., Lyons, J., Yeung, A., Ikeno, F. ELSEVIER SCIENCE INC. 2015: A161

  View details for DOI 10.1016/S0735-1097(15)60161-9

  View details for Web of Science ID 000375328800162

• Assessment of Obesity and Cardiovascular Risk in South Asians CURRENT CARDIOVASCULAR RISK REPORTS Parikh, N. I., Aurora, M. S., Dash, R., Shin, J. J., Palaniappan, L. 2015; 9 (1)

  View details for DOI 10.1007/s12170-014-0425-2

  View details for Web of Science ID 000420151200004

• Relationship between Echocardiographic and Magnetic Resonance Derived Measures of Right Ventricular Size and Function in Patients with Pulmonary Hypertension. Journal of the American Society of Echocardiography Shiran, H., Zamanian, R. T., McConnell, M. V., Liang, D. H., Dash, R., Heidary, S., Sudini, N. L., Wu, J. C., Haddad, F., Yang, P. C. 2014; 27 (4): 405-412

  Abstract

  Transthoracic echocardiographic (TTE) imaging is the mainstay of clinical practice for evaluating right ventricular (RV) size and function, but its accuracy in patients with pulmonary hypertension has not been well validated.Magnetic resonance imaging (MRI) and TTE images were retrospectively reviewed in 40 consecutive patients with pulmonary hypertension. RV and left ventricular volumes and ejection fractions were calculated using MRI. TTE areas and indices of RV ejection fraction (RVEF) were compared.The average age was 42 ± 12 years, with a majority of women (85%). There was a wide range of mean pulmonary arterial pressures (27-81 mm Hg) and RV end-diastolic volumes (111-576 mL), RVEFs (8%-67 %), and left ventricular ejection fractions (26%-72%) by MRI. There was a strong association between TTE and MRI-derived parameters: RV end-diastolic area (by TTE imaging) and RV end-diastolic volume (by MRI), R(2) = 0.78 (P < .001); RV fractional area change by TTE imaging and RVEF by MRI, R(2) = 0.76 (P < .001); and tricuspid annular plane systolic excursion by TTE imaging and RVEF by MRI, R(2) = 0.64 (P < .001). By receiver operating characteristic curve analysis, an RV fractional area change < 25% provided excellent discrimination of moderate systolic dysfunction (RVEF < 35%), with an area under the curve of 0.97 (P < .001). An RV end-diastolic area index of 18 cm(2)/m(2) provided excellent discrimination for moderate RV enlargement (area under the curve, 0.89; P < .001).Echocardiographic estimates of RV volume (by RV end-diastolic area) and function (by RV fractional area change and tricuspid annular plane systolic excursion) offer good approximations of RV size and function in patients with pulmonary hypertension and allow the accurate discrimination of normal from abnormal.

  View details for DOI 10.1016/j.echo.2013.12.011

  View details for PubMedID 24444659

• Manganese-Enhanced MRI Enables Longitudinal in vivo Tracking of Transplanted Stem Cell Viability in the Murine Myocardium Dash, R., Subramanian, A., Matsuura, Y., Sohn, I., Yeh, T., McConnell, M. V., Wu, J. C., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000332162906073

• A novel stress echocardiography pattern for myocardial bridge with invasive structural and hemodynamic correlation. Journal of the American Heart Association Lin, S., Tremmel, J. A., Yamada, R., Rogers, I. S., Yong, C. M., Turcott, R., McConnell, M. V., Dash, R., Schnittger, I. 2013; 2 (2)

  Abstract

  Patients with a myocardial bridge (MB) and no significant obstructive coronary artery disease (CAD) may experience angina presumably from ischemia, but noninvasive assessment has been limited and the underlying mechanism poorly understood. This study seeks to correlate a novel exercise echocardiography (EE) finding for MBs with invasive structural and hemodynamic measurements.Eighteen patients with angina and an EE pattern of focal end-systolic to early-diastolic buckling in the septum with apical sparing were prospectively enrolled for invasive assessment. This included coronary angiography, left anterior descending artery (LAD) intravascular ultrasound (IVUS), and intracoronary pressure and Doppler measurements at rest and during dobutamine stress. All patients were found to have an LAD MB on IVUS. The ratios of diastolic intracoronary pressure divided by aortic pressure at rest (Pd/Pa) and during dobutamine stress (diastolic fractional flow reserve [dFFR]) and peak Doppler flow velocity recordings at rest and with stress were successfully performed in 14 patients. All had abnormal dFFR (≤0.75) at stress within the bridge, distally or in both positions, and on average showed a more than doubling in peak Doppler flow velocity inside the MB at stress. Seventy-five percent of patients had normalization of dFFR distal to the MB, with partial pressure recovery and a decrease in peak Doppler flow velocity.A distinctive septal wall motion abnormality with apical sparing on EE is associated with a documented MB by IVUS and a decreased dFFR. We posit that the septal wall motion abnormality on EE is due to dynamic ischemia local to the compressed segment of the LAD from the increase in velocity and decrease in perfusion pressure, consistent with the Venturi effect.

  View details for DOI 10.1161/JAHA.113.000097

  View details for PubMedID 23591827

• A novel stress echocardiography pattern for myocardial bridge with invasive structural and hemodynamic correlation. Journal of the American Heart Association Lin, S., Tremmel, J. A., Yamada, R., Rogers, I. S., Yong, C. M., Turcott, R., McConnell, M. V., Dash, R., Schnittger, I. 2013; 2 (2)

  View details for DOI 10.1161/JAHA.113.000097

  View details for PubMedID 23591827

• DUAL CONTRAST CARDIAC MRI FOR EVALUATION OF TELMISARTAN AND AMLODIPINE COMBINATION THERAPY IN THE DIABETIC MURINE MYOCARDIAL INJURY MODEL 62nd Annual Scientific Session of the American-College-of-Cardiology Kim, P., Gong, Y., Harnish, P., Toma, I., Dash, R., Robbins, R., Yang, P. ELSEVIER SCIENCE INC. 2013: E941–E941

  View details for Web of Science ID 000316555201046

• VALIDATION OF INFARCT CHARACTERIZATION IN A PORCINE ISCHEMIA REPERFUSION INJURY MODEL 62nd Annual Scientific Session of the American-College-of-Cardiology Nakagawa, K., Ikeno, F., Matsuura, Y., Lyons, J., Nguyen, P., Wu, J., Yeung, A. C., Yang, P. C., Dash, R. ELSEVIER SCIENCE INC. 2013: E617–E617

  View details for Web of Science ID 000316555200617

• SUSTAINED RESTORATION OF LV FUNCTION IN A PORCINE ISCHEMIA-REPERFUSION INJURY MODEL USING HUMAN PLACENTAL MESENCHYMAL STEM CELLS AND MANGANESE-ENHANCED MRI 62nd Annual Scientific Session of the American-College-of-Cardiology Dash, R., Kim, P., Matsuura, Y., Ikeno, F., Lyons, J., Ge, X., Metzler, S., Huang, N., Nguyen, P., Wu, J. C., Cooke, J., Luiz-Rozano, P., Robbins, R., McConnell, M., Yeung, A., Harnish, P., Yang, P. ELSEVIER SCIENCE INC. 2013: E1142–E1142

  View details for Web of Science ID 000316555201247

• REGENERATIVE CHANGES OF THE PERI-INFARCT INJURY ALLOWS SUSTAINED RESTORATION OF THE INJURED MYOCARDIUM 62nd Annual Scientific Session of the American-College-of-Cardiology Kim, P., Gong, Y., Ge, X., Harnish, P., Dash, R., Robbins, R., Yang, P. ELSEVIER SCIENCE INC. 2013: E1074–E1074

  View details for Web of Science ID 000316555201179

• Near infrared imaging and photothermal ablation of vascular inflammation using single-walled carbon nanotubes. Journal of the American Heart Association Kosuge, H., Sherlock, S. P., Kitagawa, T., Dash, R., Robinson, J. T., Dai, H., McConnell, M. V. 2012; 1 (6)

  Abstract

  Macrophages are critical contributors to atherosclerosis. Single-walled carbon nanotubes (SWNTs) show promising properties for cellular imaging and thermal therapy, which may have application to vascular macrophages.In vitro uptake and photothermal destruction of mouse macrophage cells (RAW264.7) were performed with SWNTs (14.7 nmol/L) exposed to an 808-nm light source. SWNTs were taken up by 94 ± 6% of macrophages, and light exposure induced 93 ± 3% cell death. In vivo vascular macrophage uptake and ablation were then investigated in carotid-ligated FVB mice (n=33) after induction of hyperlipidemia and diabetes. Two weeks postligation, near-infrared fluorescence (NIRF) carotid imaging (n=12) was performed with SWNT-Cy5.5 (8 nmol of Cy5.5) given via the tail vein. Photothermal heating and macrophage apoptosis were evaluated on freshly excised carotid arteries (n=21). NIRF of SWNTs showed higher signal intensity in ligated carotids compared with sham, confirmed by both in situ and ex vivo NIRF imaging (P<0.05, ligation versus sham). Immunofluorescence staining showed colocalization of SWNT-Cy5.5 and macrophages in atherosclerotic lesions. Light (808 nm) exposure of freshly excised carotids showed heating and induction of macrophage apoptosis in ligated left carotid arteries with SWNTs, but not in control groups without SWNTs or without light exposure.Carbon nanotubes accumulate in atherosclerotic macrophages in vivo and provide a multifunctional platform for imaging and photothermal therapy of vascular inflammation.

  View details for DOI 10.1161/JAHA.112.002568

  View details for PubMedID 23316318

• Relationship Between Echocardiographic and MRI-derived Measures of RV Size and Function in Patients with Pulmonary Arterial Hypertension Shiran, H., Liang, D. H., Dash, R., Heidary, S., Sudini, N. L., Seo, H., Wu, J. C., Haddad, F., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885008050

• Myocardial Bridging: Novel Insights from Exercise Echocardiographic Correlations with Hemodynamic Measurements - The Venturi Effect Lin, S., Tremmel, J., Yamada, R., Yong, C. M., Rogers, I. S., McConnell, M. V., Dash, R., Schnittger, I. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885004331

• The Human Amniotic Mesenchymal Stem Cell-derived Ipscs Survive and Restore the Injured Hearts in an Immunocompetent Mouse Model of Myocardial Injury Ge, X., Chung, W., Kim, P. J., Gong, Y., Chang, P., Robbins, R., Dash, R., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885008107

• Theranostic effect of serial manganese-enhanced magnetic resonance imaging of human embryonic stem cell derived teratoma MAGNETIC RESONANCE IN MEDICINE Chung, J., Dash, R., Kee, K., Barral, J. K., Kosuge, H., Robbins, R. C., Nishimura, D., Reijo-Pera, R. A., Yang, P. C. 2012; 68 (2): 595-599

  Abstract

  Although human embryonic stem cell (hESC) hold therapeutic potential, teratoma formation has deterred clinical translation. Manganese (Mn(2+)) enters metabolically active cells through voltage-gated calcium channels and subsequently, induces T(1) shortening. We hypothesized that serial manganese-enhanced MRI would have theranostic effect to assess hESC survival, teratoma formation, and hESC-derived teratoma reduction through intracellular accumulation of Mn(2+). Firefly luciferase transduced hESCs (hESC-Lucs) were transplanted into severe combined immunodeficient mouse hindlimbs to form teratoma. The chemotherapy group was injected with MnCl(2) intraperitoneally three times a week. The control group was given MnCl(2) only prior to manganese-enhanced MRI. Longitudinal evaluation by manganese-enhanced MRI and bioluminescence imaging was performed. The chemotherapy group showed significant reduction in the teratoma volume and luciferase activity at weeks 6 and 8. Histology revealed increased proportion of dead cells and caspase 3 positive cells in the chemotherapy group. Systemic administration of MnCl(2) enabled simultaneous monitoring and elimination of hESC-derived teratoma cells by higher intracellular accumulation of Mn(2+).

  View details for DOI 10.1002/mrm.23262

  View details for PubMedID 22190225

• Cardiovascular Magnetic Resonance Imaging Elucidates Genotype-Phenotype Relationships in Patients with Hypertrophic Cardiomyopathy Scientific Sessions of the American-Heart-Association/Resuscitation Science Symposium Heidary, S., Wheeler, M. T., Bennett, M. V., Chung, J., Pavlovic, A., Parent, M., Dash, R., McConnell, M. V., Ashley, E. A., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2011

  View details for Web of Science ID 000299738705331

• In vivo Molecular MRI of Cell Survival and Teratoma Formation Following Embryonic Stem Cell Transplantation Into the Injured Murine Myocardium MAGNETIC RESONANCE IN MEDICINE Chung, J., Kee, K., Barral, J. K., Dash, R., Kosuge, H., Wang, X., Weissman, I., Robbins, R. C., Nishimura, D., Quertermous, T., Reijo-Pera, R. A., Yang, P. C. 2011; 66 (5): 1374-1381

  Abstract

  Embryonic stem cells (ESCs) have shown the potential to restore cardiac function after myocardial injury. Superparamagnetic iron oxide nanoparticles (SPIO) have been widely employed to label ESCs for cellular MRI. However, nonspecific intracellular accumulation of SPIO limits long-term in vivo assessment of the transplanted cells. To overcome this limitation, a novel reporter gene (RG) has been developed to express antigens on the ESC surface. By employing SPIO-conjugated monoclonal antibody against these antigens (SPIO-MAb), the viability of transplanted ESCs can be detected in vivo. This study aims to develop a new molecular MRI method to assess in vivo ESC viability, proliferation, and teratoma formation. The RG is designed to express 2 antigens (hemagglutinin A and myc) and luciferase on the ESC surface. The two antigens serve as the molecular targets for SPIO-MAb. The human and mouse ESCs were transduced with the RG (ESC-RGs) and transplanted into the peri-infarct area using the murine myocardial injury model. In vivo MRI was performed following serial intravenous administration of SPIO-MAb. Significant hypointense signal was generated from the viable and proliferating ESCs and subsequent teratoma. This novel molecular MRI technique enabled in vivo detection of early ESC-derived teratoma formation in the injured murine myocardium.

  View details for DOI 10.1002/mrm.22929

  View details for PubMedID 21604295

• In vivo Kinetics of Embryonic Stem Cell Viability Following Transplantation Into the Injured Murine Myocardium 82nd National Conference and Exhibitions and Scientific Sessions of the American-Heart-Association Chung, J., Kee, K., Barral, J. K., Dash, R., Weissman, I., Quertermous, T., Robbins, R. C., Nishimura, D. G., Reijo-Pera, R. A., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2009: S310–S311

  View details for Web of Science ID 000271831500052

• Magnetic Resonance Imaging With Targeted Iron-Oxide Labeling Detects Differential Cardiac Cell Survival After Doxorubicin and Myocardial Infarction in Culture and In Vivo Dash, R., Chan, T., Yamada, M., Paningbatan, M., Myagmar, B., Swigart, P. M., Yang, P. C., Simpson, P. C. ELSEVIER SCIENCE INC. 2009: A304

  View details for Web of Science ID 000263864201261

• Magnetic Resonance Imaging with Iran-Oxide Labeling Detects Differential Cell Survival after Doxorubicin Exposure in Cardiac Myocytes, Fibroblasts, and Stem Cells Dash, R., Chan, T., Yamada, M., Paningbatan, M., Swigart, P. M., Myagmar, B., Yang, P. C., Simpson, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2008: S996

  View details for Web of Science ID 000262104503698

• The contractile and neurohormonal roles of phospholamban in heart failure 17th World Heart Congress Dash, R., Kranias, E. G. KLUWER ACADEMIC PUBLISHERS. 2003: 135–152

  View details for Web of Science ID 000183540400009

• The enhanced contractility of the phospholamban-deficient mouse heart persists with aging JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Slack, J. P., Grupp, I. L., Dash, R., Holder, D., Schmidt, A., Gerst, M. J., Tamura, T., Tilgmann, C., James, P. F., Johnson, R., Gerdes, A. M., Kranias, E. G. 2001; 33 (5): 1031-1040

  Abstract

  J. P. Slack, I. L. Grupp, R. Dash, D. Holder, A. Schmidt, M. J. Gerst, T. Tamura, C. Tilgmann, P. F. James, R. Johnson, A. M. Gerdes and E. G. Kranias. The Enhanced Contractility of the Phospholamban-deficient Mouse Heart Persists with Aging. Journal of Molecular and Cellular Cardiology (2001) 33, 1031-1040. Phospholamban ablation in the mouse is associated with significant increases in cardiac contractility. To determine whether this hyperdynamic function persists through the aging process, a longitudinal examination of age-matched phospholamban-deficient and wild-type mice was employed. Kaplan-Meier survival curves indicated no significant differences between phospholamban-deficient and wild-type mice over the first year. Examination of cardiac function revealed significant increases in the rates of contraction (+dP/dt) and relaxation (-dP/dt) in phospholamban-deficient hearts compared with their wild-type counterparts at 3, 6, 12, 18 and 24 months of age. Quantitative immunoblotting indicated that the expression levels of the sarcoplasmic reticulum Ca(2+)-ATPase were not altered in wild-type hearts, while they were significantly decreased at 12 months (40%) and 18 months (20%) in phospholamban-deficient hearts. These findings on the persistence of hyperdynamic cardiac function over the long term suggest that phospholamban may constitute an important target for treatment in heart disease.

  View details for DOI 10.1006/jmcc.2001.1370

  View details for Web of Science ID 000168769200016

  View details for PubMedID 11343424

• Altering the receptor-effector ratio by transgenic overexpression of type V adenylyl cyclase: Enhanced basal catalytic activity and function without increased cardiomyocyte beta-adrenergic signalling BIOCHEMISTRY Tepe, N. M., Lorenz, J. N., Yatani, A., Dash, R., Kranias, E. G., Dorn, G. W., Liggett, S. B. 1999; 38 (50): 16706-16713

  Abstract

  The limiting element in beta-adrenergic receptor (betaAR)-G(s)-adenylyl cyclase (AC) signal transduction in the cardiomyocyte is not known, but it has been proposed that the level of adenylyl cyclase expression constrains betaAR signaling. To alter the above equilibrium, type V AC was overexpressed in a myocyte-specific manner in the hearts of transgenic mice using the alpha-myosin heavy chain promoter. Expression of type V AC was approximately 75% over endogenous levels as quantitated by [(3)H]forskolin binding. Functional activity of the transgene product was evident in cardiac membrane AC studies, where basal (45 +/- 11 vs 19 +/- 5 pmol min(-)(1) mg(-)(1)) and forskolin+Mn(2+) (695 +/- 104 vs 386 +/- 34 pmol min(-)(1) mg(-)(1)) stimulated activities were increased compared to activities in nontransgenic (NTG) littermates. However, while isoproterenol stimulated activities were higher (74 +/- 12 vs 46 +/- 9.8 pmol min(-)(1) mg(-)(1)), the fold stimulation over basal was not increased in ACV overexpressors compared to NTG (line 14.3 = 2.29 +/- 0.44-fold, line 15.1 = 1.70 +/- 0.1-fold, NTG = 2.62 +/- 0.18-fold). Similarly, in whole cell patch-clamp studies, betaAR-mediated opening of L-type Ca(2+) channels was not found to be enhanced in transgenic ACV myocytes (225 +/- 15 vs 216 +/- 10% of basal currents). Basal and isoproterenol stimulated PKA activities were elevated in the ACV mice compared to NTG, but again the extent of stimulation over basal was not enhanced. Phosphorylated phospholamban was approximately 2-fold greater in myocytes from ACV hearts compared to NTG, indicating that distal elements of the contractile cascade are activated by AC overexpression. ACV mice displayed increased heart rates and fractional shortening as assessed by echocardiography. However, in vivo hemodynamic studies revealed that heart rate and contractility responses to agonist infusion were not enhanced in ACV mice compared to NTG. We conclude that at native stoichiometries, the levels of adenylyl cyclase influence basal activities and cardiac function, but do not constrain betaAR signaling in the cardiomyocyte.

  View details for Web of Science ID 000084289300034

  View details for PubMedID 10600134

• Influence of transgenic overexpression of phospholamban on postextrasystolic potentiation JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Hoit, B. D., Tramuta, D. A., Kadambi, V. J., Dash, R., Ball, N., Kranias, E. G., Walsh, R. A. 1999; 31 (11): 2007-2015

  Abstract

  Twelve mice with PLB overexpression (PLBOE), and 11 isogenic FVB/N wild-type (WT) controls, were anesthetized and instrumented with a 1.4 F Millar catheter in the LV and a 1 F pacemaker in the right atrium. At a cycle length of 200 ms and a fixed extrastimulus of 120 ms, extrastimuli with increasing intervals (PESI) up to 1000 ms were introduced, and the peak rates of LV isovolumic contraction (+/- dP/dtmax) were normalized and fit to monoexponential equations. In a subset of animals, the protocols were repeated after ryanodine (4 ng/g) was given to deplete SR Ca2+ stores. The time constant and the plateau of the exponential curve fits were significantly greater in PLBOE than WT (107.8 +/- 7.0 v 75.2 +/- 5.5 ms and 1.39 +/- 0.03 v 1.08 +/- 0.02, both P < 0.05). At 200, 600 and 1000 ms, the normalized dP/dt was significantly greater in PLBOE than WT. After ryanodine, normalized dP/dt was significantly decreased in PLBOE, but unchanged in WT. The protein levels of the sodium-calcium exchanger normalized to calsequestrin were increased 3.7 +/- 0.3-fold in PLBOE compared to controls. In conclusion, the phospholamban level is a critical determinant of postextrasystolic potentiation in this transgenic model, and is differentially impaired by ryanodine at long diastolic intervals in PLBOE v controls. These differences may be due in part to changes in the protein level and resultant activity of the sodium calcium exchanger.

  View details for Web of Science ID 000083749100006

  View details for PubMedID 10591027

• Astressin, a novel and potent CRF antagonist, is neuroprotective in the hippocampus when administered after a seizure BRAIN RESEARCH Maecker, H., Desai, A., Dash, R., RIVIER, J., Vale, W., Sapolsky, R. 1997; 744 (1): 166-170

  Abstract

  Corticotropin-releasing factor (CRF), the principle hypothalamic regulator of the adrenocortical axis, also functions as a neurotransmitter. In this latter role, CRF causes electrophysiological activation and epileptiform activity in various brain regions. That finding, coupled with the observation that CRF mRNA is induced in endangered brain regions following necrotic insults, suggests that the peptide might contribute to necrotic neuron loss. Supporting that, a number of studies have shown that CRF antagonists decrease ischemic or excitotoxic damage to neurons. In the present report, we demonstrate the considerable neuroprotective potential of a novel and potent CRF antagonist, astressin, against kainic acid-induced excitotoxic seizures. Intracerebroventricular infusion of the peptide both 30 min before and 10 min after seizures decreased damage in some hippocampal cell fields by as much as 84%, a magnitude of protection greater than reported for other CRF antagonists against other models of necrotic neuronal injury. Administration of astressin was done against both local microinfusion (0.035 microgram) or systemic infusion (10 mg/kg body weight) of the excitotoxin; furthermore, the peptide protected even if administered only 10 min following excitotoxin exposure. This fulfills a critical prerequisite for any eventual therapeutic use of CRF antagonists, namely that they need not be administered in anticipation of a neurological insult.

  View details for Web of Science ID A1997WD51800023

  View details for PubMedID 9030428

• Overexpression of the glucose transporter gene with a Herpes simplex viral vector protects striatal neurons against stroke JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Lawrence, M. S., Sun, G. H., Kunis, D. M., Saydam, T. C., Dash, R., Ho, D. Y., Sapolsky, R. M., Steinberg, G. K. 1996; 16 (2): 181-185

  Abstract

  Herpes simplex virus vectors bearing a glucose transporter (GT) gene and a marker gene were found to protect neurons against a 1-h focal ischemic insult. Rats receiving the GT vector v alpha22beta gal alpha4GT exhibited a 67.4 +/- 35.3% survival of virally targeted neurons in the ischemic hemisphere compared with the contralateral control (n = 7), whereas rats receiving a control vector exhibited only 32.8 +/- 17.9% survival (n = 9). This significant improvement in survival (105%, p=0.022) suggests that energy failure is an important contributor to the neuropathology of ischemic damage in the striatum, and that it can be alleviated by gene transfer. This is the first demonstration of protection against ischemic cerebral injury by the direct transfer of GT genes to neurons.

  View details for Web of Science ID A1996TW39300001

  View details for PubMedID 8594048

• A herpes simplex virus vector overexpressing the glucose transporter gene protects the rat dentate gyrus from an antimetabolite toxin EXPERIMENTAL NEUROLOGY Dash, R., Lawrence, M., Ho, D., Sapolsky, R. 1996; 137 (1): 43-48

  Abstract

  The use of herpes simplex virus vectors offers an attractive means for the in vitro and in vivo transfer of novel genes into postmitotic neurons. Such an approach allows for the introduction of genes with the potential to protect neurons from necrotic insults. Toward that end, we have previously constructed a bicistronic herpes viral vector expressing the gene for the Glut-1 rat brain glucose transporter (GT), along with the Escherichia coli lacZ reporter gene. We observed that this vector enhances glucose uptake both in primary hippocampal cultures and in the hippocampus itself. Moreover, we have found that this vector will protect a variety of types of cultured neurons from necrotic insults and protect hippocampal neurons in vivo from seizure-induced damage. In the present report, we further demonstrate the neuroprotective potential of this GT-expressing vector. 3-Acetylpyridine, an electron transport uncoupler which is preferentially toxic to the dentate gyrus, was microinfused into the dorsal hippocampus of rats. Infection of dentate neurons with GT vectors at the time of exposure to the toxin significantly decreased damage, whereas infection with a physiologically neutral control vector did not. Moreover, there was a window of opportunity for this intervention, as microinfusion of the GT-expressing vector up to 1 h, but not 4 h, after the insult was still neuroprotective.

  View details for Web of Science ID A1996TQ62700005

  View details for PubMedID 8566211

• HERPES-SIMPLEX VIRUS VECTORS OVEREXPRESSING THE GLUCOSE-TRANSPORTER GENE PROTECT AGAINST SEIZURE-INDUCED NEURON LOSS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lawrence, M. S., Ho, D. Y., Dash, R., Sapolsky, R. M. 1995; 92 (16): 7247-7251

  Abstract

  We have generated herpes simplex virus (HSV) vectors vIE1GT and v alpha 4GT bearing the GLUT-1 isoform of the rat brain glucose transporter (GT) under the control of the human cytomegalovirus ie1 and HSV alpha 4 promoters, respectively. We previously reported that such vectors enhance glucose uptake in hippocampal cultures and the hippocampus. In this study we demonstrate that such vectors can maintain neuronal metabolism and reduce the extent of neuron loss in cultures after a period of hypoglycemia. Microinfusion of GT vectors into the rat hippocampus also reduces kainic acid-induced seizure damage in the CA3 cell field. Furthermore, delivery of the vector even after onset of the seizure is protective, suggesting that HSV-mediated gene transfer for neuroprotection need not be carried out in anticipation of neurologic crises. Using the bicistronic vector v alpha 22 beta gal alpha 4GT, which coexpresses both GT and the Escherichia coli lacZ marker gene, we further demonstrate an inverse correlation between the extent of vector expression in the dentate and the amount of CA3 damage resulting from the simultaneous delivery of kainic acid.

  View details for Web of Science ID A1995RM72200024

  View details for PubMedID 7638175

• HERPES-SIMPLEX VIRUS VECTOR SYSTEM - ANALYSIS OF ITS IN-VIVO AND IN-VITRO CYTOPATHIC EFFECTS JOURNAL OF NEUROSCIENCE METHODS Ho, D. Y., Fink, S. L., Lawrence, M. S., Meier, T. J., Saydam, T. C., Dash, R., Sapolsky, R. M. 1995; 57 (2): 205-215

  Abstract

  With its natural propensity to infect and establish life-long latency in neurons, herpes simplex virus type 1 (HSV-1) has been successfully employed by various laboratories as vectors for gene transfer into neurons. However, analysis of its cytopathic effects in vivo and in vitro has been limited. In this study, we examined the cytopathic effects of 2 HSV-1 alpha 4 mutants (ts756 and d120) on adult rat hippocampus and striatum and of d120 on hippocampal neurons in culture. We assessed damage by stringent counting of surviving neurons after infection and demonstrated that while neither ts756 nor d120 infection resulted in any gross anatomical or behavioral changes of the animals, ts756, but not d120, produced a significant amount of damage in the CA4 cell field and dentate gyrus of the hippocampus. Thus, since crude examination is insufficient to detect subtle but significant degrees of neuron loss, the cytopathic effects of HSV or any vector system must be carefully analyzed. Furthermore, we also observed that uninfected cell lysates damaged neurons, both in vivo and in vitro. This cytotoxicity occurred within the first 24 h post-inoculation and probably arose through the activation of glutamate receptors. For the preparation of HSV vectors, purification of the virus from soluble cellular components by a simple pelleting step can significantly decrease such acute toxicity.

  View details for Web of Science ID A1995QU14500010

  View details for PubMedID 7609584