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Abnormal red blood cell ion transport and hypertension. The People's Gas Company study.
- M Trevisan,
- D Ostrow,
- R Cooper,
- K Liu,
- S Sparks,
- A Okonek,
- E Stevens,
- J Marquardt and
- J Stamler
Hypertension Volume 5, Issue 31 May 1983

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A population-based survey of 134 white men, recruited from the Chicago People's Gas Company labor force, was carried out to examine the association between sodium-lithium (Na-Li) countertransport and hypertension. Of the 134 participants in this industry-sponsored periodic health examination, 64 were normotensive and 70 were either taking antihypertensive medications or had a systolic pressure greater than or equal to 140 or a diastolic pressure greater than or equal to 90 mm Hg. The hypertensives were older and more overweight. Countertransport was significantly higher in hypertensives than in normotensives. Among the three subgroups of hypertensives--untreated, borderline (140/90 to 160/95 mm Hg), untreated definite (over 160/95 mm Hg), and treated--an increase in countertransport was consistently observed, significant for the latter two groups. The relationship between countertransport and hypertension was independent of overweight, with countertransport being significantly related to both blood pressure and overweight. Altered ion transport may play an important role in the etiology and/or pathophysiology of hypertension.
Circulating MicroRNA-21 Correlates With Left Atrial Low-Voltage Areas and Is Associated With Procedure Outcome in Patients Undergoing Atrial Fibrillation Ablation
- Qifeng Zhou,
- Carole Maleck,
- Saskia N.I. von Ungern-Sternberg,
- Balram Neupane,
- David Heinzmann,
- Jonathan Marquardt,
- Martin Duckheim,
- Christian Scheckenbach,
- Fabian Stimpfle,
- Meinrad Gawaz,
- Jürgen Schreieck,
- Peter Seizer and
- Michael Gramlich
Circulation: Arrhythmia and Electrophysiology Volume 11, Issue 61 June 2018

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Background:Atrial fibrosis is a hallmark of arrhythmogenic structural remodeling in patients with persistent atrial fibrillation (AF) and is negatively correlated with procedure outcome in patients undergoing ablation. However, noninvasive methods to determine the extent of atrial fibrosis are limited. Here, we used microRNA (miRNA) expression analysis to detect markers of left atrial low-voltage areas (LVAs) in patients with persistent AF undergoing catheter ablation.Methods:We performed 3-dimensional voltage mapping in 102 patients (average age 62.1±13.1 years, CHA₂DS₂-VASc score of 2.3±1.6, LA size 41.5±5.7 mm) undergoing ablation for persistent AF and determined the extent of left atrial low-voltage. LVAs were defined if bipolar electrogram amplitudes were <0.5 mV during sinus rhythm. Before ablation, we obtained a blood sample, isolated miRNAs, and profiled them on a miRCURY LNA Universal RT microRNA PCR Human panel.Results:Sixty-nine miRNAs were identified in all samples, with an average of 123 miRNAs detectable per sample. We found that the serum concentration of miR-21, a miRNA that has been previously linked to cardiac fibrosis development, was strongly associated with the extent of LVAs determined by voltage mapping. We could confirm that LVAs were negatively correlated with ablation success in a 1-year follow-up. In addition, miR-21 serum levels were associated with AF-free survival after catheter ablation.Conclusions:Circulating miR-21 correlates with left atrial LVAs and is associated with procedure outcome in patients with persistent AF undergoing ablation.
Independent contribution of electrocardiographic abnormalities to risk of death from coronary heart disease, cardiovascular diseases and all causes. Findings of three Chicago epidemiologic studies.
- B L Cedres,
- K Liu,
- J Stamler,
- A R Dyer,
- R Stamler,
- D M Berkson,
- O Paul,
- M Lepper,
- H A Lindberg,
- J Marquardt,
- E Stevens,
- J A Schoenberger,
- R B Shekelle,
- P Collette and
- D Garside
Circulation Volume 65, Issue 11 January 1982

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Abstract 14657: Intermuscular Fat is Independently Associated With Coronary Microvascular Dysfunction and Adverse Cardiovascular Outcomes in Patients With No Obstructive CAD
- Ana Carolina A Souza,
- Amelie S Troschel,
- Jan P Marquardt,
- Sanjay Divakaran,
- Jenifer Brown,
- Leanne Barrett,
- Laurel Martell,
- Courtney Bibbo,
- Jon Hainer,
- Ron Blankstein,
- Sharmila Dorbala,
- MARCELO F DI CARLI,
- Florian J Fintelmann and
- Viviany R Taqueti
Circulation Volume 142, Issue Suppl_317 November 2020

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Introduction: Intermuscular adipose tissue (IMAT) reflects skeletal muscle quality and is associated with inflammation, a key determinant in cardiometabolic disease. Coronary flow reserve (CFR), a marker of coronary microvascular dysfunction (CMD), is independently associated with BMI, inflammation and risk of heart failure, myocardial infarction and death. Using a novel neural networks algorithm for body composition analysis, we sought to investigate the relationship between skeletal muscle quality, CMD and cardiovascular outcomes.Methods: Consecutive patients (N=669) undergoing evaluation for CAD with cardiac stress PET demonstrating normal perfusion and preserved LVEF were followed over median 6 years for events (MACE), including death and hospitalization for myocardial infarction or heart failure. CFR was calculated as the stress/rest myocardial blood flow ratio. Subcutaneous fat (SAT) and IMAT areas (cm²) were obtained from PET attenuation correction CTs using a fully automated algorithm validated by manual segmentation at T10 and T12 levels, respectively.Results: Median age was 63 years, 70% were female and 46% nonwhite. Nearly half of patients were obese (46% with BMI 30-61) and BMI correlated closely with SAT and IMAT (r=0.8 and 0.7, respectively, p<0.001). Independent of age, sex, race, BMI, LVEF and hypertension, CFR was associated with IMAT (β -0.10, p=0.047). In adjusted analyses, both CFR and increased IMAT were independently associated with MACE [HR 1.6 (1.1-2.4) per -1U CFR and 1.5 (1.2-1.7) per +10 cm² IMAT, p≤0.01]. Patients with both CMD and poor muscle quality demonstrated highest risk of MACE (adjusted p<0.02).Conclusion: Increased intermuscular fat is associated with CMD and adverse cardiovascular outcomes independently of BMI and traditional risk factors. Combined assessment of skeletal muscle quality and coronary microvascular function may help to redefine at-risk cardiometabolic phenotypes.
Relationship of education to major risk factors and death from coronary heart disease, cardiovascular diseases and all causes, Findings of three Chicago epidemiologic studies.
- K Liu,
- L B Cedres,
- J Stamler,
- A Dyer,
- R Stamler,
- S Nanas,
- D M Berkson,
- O Paul,
- M Lepper,
- H A Lindberg,
- J Marquardt,
- E Stevens,
- J A Schoenberger,
- R B Shekelle,
- P Collette,
- S Shekelle and
- D Garside
Circulation Volume 66, Issue 61 December 1982

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DR. GILBERT H. MARQUARDT 1903 - 1965
Circulation Volume 33, Issue 5s21 May 1966

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Noninvasive Assessment of the Ventricular Relaxation Time Constant (τ) in Humans by Doppler Echocardiography
Circulation Volume 95, Issue 17 January 1997

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Background The time constant of ventricular relaxation (τ) is a quantitative measure of diastolic performance requiring intraventricular pressure recording. This study validates in humans an equation relating τ to left ventricular pressure at peak −dP/dt (P₀), pressure at mitral valve opening (P_MV), and isovolumic relaxation time (IVRT_inv). The clinically obtainable parameters peak systolic blood pressure (P_s), mean left atrial pressure (P_LA), and Doppler-derived IVRT (IVRT_Dopp) are then substituted into this equation to obtain τ_Dopp noninvasively.Methods and Results High-fidelity left atrial and left ventricular pressure recordings with simultaneous Doppler by transesophageal echocardiography were obtained from 11 patients during cardiac surgery. Direct curve fitting to the left ventricular pressure trace by Levenberg-Marquardt regression assuming a zero asymptote generated τ_LM, the “gold standard” against which τ_calc {IVRT_inv/[ln(P₀)−ln(P_MV)]} and τ_Dopp {IVRT_Dopp/[ln(P_s)−ln(P_LA)]} were compared. For 123 cycles analyzed in 18 hemodynamic states, mean τ_LM was 53.8±12.9 ms. τ_calc (51.5±11 ms) correlated closely with this standard (r=.87, SEE=5.5 ms). Noninvasive τ_Dopp (43.8±11 ms) underestimated τ_LM but exhibited close linear correlation (n=88, r=.75, SEE=7.5 ms). Substituting P_LA=10 mm Hg into the equation yielded τ₁₀ (48.7±15 ms), which also closely correlated with the standard (r=.62, SEE=11.6 ms).Conclusions The previously obtained analytical expression relating IVRT, invasive pressures, and τ is valid in humans. Furthermore, a more clinically obtainable, noninvasive method of obtaining τ also closely predicts this important measure of diastolic function.
Lower Rates of Intervention for Symptomatic Carotid Stenosis in Women Than in Men Reflect Differences in Disease Incidence: A Population-Based Study
- Lars Marquardt,
- Jack F. Fairhead and
- Peter M. Rothwell
Stroke Volume 41, Issue 11 January 2010

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Background and Purpose— Although there is little sex difference in the age-specific incidence of transient ischemic attack (TIA) and stroke, substantially more men than women undergo endarterectomy/stenting for symptomatic carotid stenosis. Sexism in referral for investigation or intervention has been proposed as an explanation; however, a lower incidence of carotid disease in women or reluctance to undergo intervention might also be responsible.Methods— We determined the sex-specific incidence of symptomatic carotid stenosis and subsequent endarterectomy/stenting from 2002 to 2009 in consecutive patients with TIA or nondisabling ischemic stroke in the Oxford Vascular Study. We studied equivalent data from routine clinical practices in the wider Oxfordshire population.Results— There was no sex difference in age-specific referral rates for carotid imaging in the Oxford Vascular Study (n=616; age-adjusted relative rate [RR] for males vs females=1.08; 95% CI, 0.79 to 1.46; P=0.64). However, rates of 50% to 99% symptomatic carotid stenosis were higher in men (RR=1.89; 95% CI, 1.31 to 2.71; P=0.0005). The same was seen in imaged patients (n=575) in the wider Oxfordshire population (RR=1.82; 95% CI, 1.31 to 2.53; P=0.003) and in pooled data (RR=1.87; 95% CI, 1.32 to 2.64; P=0.0003). Rates of symptomatic carotid occlusion were also higher in men in both populations (RR=3.19; 95% CI, 1.95 to 5.23; P<0.0001). Consequently, although men were more likely to undergo carotid intervention (RR=1.98; 95% CI, 1.43 to 2.75; P<0.0001), the proportion of patients with 50% to 99% symptomatic carotid stenosis who received intervention was similar for men and women (odds ratio=1.13; 95% CI, 0.57 to 2.25; P=0.72).Conclusion— Lower rates of intervention for 50% to 99% symptomatic carotid stenosis in women can be explained by sex differences in population-based incidence. We found no evidence of any investigation or intervention bias.
Low Risk of Ipsilateral Stroke in Patients With Asymptomatic Carotid Stenosis on Best Medical Treatment: A Prospective, Population-Based Study
- Lars Marquardt,
- Olivia C. Geraghty,
- Ziyah Mehta and
- Peter M. Rothwell
Stroke Volume 41, Issue 11 January 2010

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Background and Purpose— The annual risk of ischemic stroke distal to ≥50% asymptomatic carotid stenoses was ≈2% to 3% in early cohort studies and subsequent randomized trials of endarterectomy. This risk might have fallen in recent years owing to improvements in medical treatment, but there are no published prognostic data from studies initiated within the last 10 years.Methods— In a population-based study of all patients with transient ischemic attack (TIA) or stroke in the Oxford Vascular Study, we studied the risk of TIA and stroke in patients with ≥50% contralateral asymptomatic carotid stenoses recruited consecutively from 2002 to 2009 and given intensive contemporary medical treatment.Results— Of 1153 consecutively imaged patients presenting with stroke or TIA, 101 (8.8%) had ≥50% asymptomatic carotid stenoses (mean age, 75 years; 39% women; 40% age ≥80 years). During 301 patient-years of follow-up (mean, 3 years), there were 6 ischemic events in the territory of an asymptomatic stenosis, 1 minor stroke (initially 50% to 69% stenosis), and 5 TIAs (2 initially 50% to 69% stenosis; 3 to 70% to 99% stenosis), 3 of which led to subsequent endarterectomy. The average annual event rates on medical treatment were 0.34% (95% CI, 0.01 to 1.87) for any ipsilateral ischemic stroke, 0% (95% CI, 0.00 to 0.99) for disabling ipsilateral stroke, and 1.78% (95% CI, 0.58 to 4.16) for ipsilateral TIA.Conclusions— In the first study of the prognosis of ≥50% asymptomatic carotid stenosis to be initiated in the last 10 years, the risk of stroke on intensive contemporary medical treatment was low. Larger studies are required to determine whether this apparent improvement in prognosis is generalizable.
Abstract TP223: Characterizing Ischemic Stroke and Hemorrhagic Conversion in Infectious Endocarditis
- Robert J Marquardt,
- Sung-Min Cho,
- Lucy Zhang,
- Prateek Thatikunta,
- Ken Uchino and
- Dolora Wisco
Stroke Volume 48, Issue suppl_11 February 2017

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Introduction: Ischemic stroke is a common complication of infective endocarditis (IE) and can delay valve surgery. Identifying risk factors for acute ischemic stroke (AIS) and hemorrhagic conversion may help in perioperative risk assessment of these patients.Methods: Retrospective analysis was done on 116 consecutive patients with IE seen by stroke neurology at a tertiary center from January 2015 through July 2016. Clinical and radiographic characteristics were collected in a population whose initial evaluation was for acute stroke management or preoperative risk evaluation. Descriptive statistics were used to identify risk factors for AIS, defined as clinical or silent infarct, both with and without hemorrhagic conversion.Results: Among 116 patients with IE, AIS occurred in 82 (70.6%) with a median NIH Stroke Scale of 3 (interquartile range (IQR) 0-12) and a median MRI volume of 13.5mL (IQR 1.4-42mL). Of AIS patients, 25 (30%) had silent infarct, 6 (7%) had concurrent primary ICH without a clear ischemic component and 25 (30%) had hemorrhagic conversion. AIS was associated with remote stroke on imaging (OR 1.27), history of diabetes (OR 1.22), and &gt 1 vegetation on echocardiogram (OR 1.29), but not history of atrial fibrillation, microhemorrhages or mycotic aneurysm on imaging, MRI enhancing lesions, aortic versus mitral valve involvement, vegetation size, organism involved, IV drug abuse, or pre-admission antithrombotic use. Microhemorrhages on MRI susceptibility-weighted images occurred in 66 (80%) AIS patients, and was associated with hemorrhagic conversion (OR 1.35). Mycotic aneurysm was found in 4 patients with hemorrhagic conversion, but this was not significant (OR 1.0). A total of 48 AIS patients (58.5%) underwent valve surgery. Additional stroke occurred while awaiting surgery in 10 AIS patients (OR 1.20), 6 were new ischemic stroke and 4 were new ICH. Post-operatively there were 1 new AIS and 3 new ICH complications.Conclusion: The incidence of acute ischemic stroke in our population was 70.6%, with a third being silent infarcts. Hemorrhagic conversion occurred in 30% and was associated with cerebral microhemorrhages.
Course of Platelet Activation Markers After Ischemic Stroke
- Lars Marquardt,
- Andreas Ruf,
- Ulrich Mansmann,
- Ralph Winter,
- Matthias Schuler,
- Florian Buggle,
- Horst Mayer and
- Armin J. Grau
Stroke Volume 33, Issue 111 November 2002

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Background and Purpose— The aim of this study was to evaluate the time course of platelet activation after ischemic stroke and to investigate whether platelet activation and inflammation are correlated with each other.Methods— We serially determined expression of p-selectin (CD62p) and lysosome-associated membrane protein (CD63) by platelets using flow cytometry at 10 time points between days 1 and 90 in patients after ischemic stroke (n=50), in healthy subjects (n=30), and in risk factor control subjects (n=20). Furthermore, we correlated leukocyte count, C-reactive protein, and fibrinogen levels with platelet activation markers.Results— CD62p and CD63 expression was higher on day 1 after stroke than in both control groups (P<0.005 for both). CD62p expression rapidly declined, whereas CD63 expression remained significantly elevated until day 90. Stroke severity and different medication for secondary stroke prevention did not influence CD62p or CD63 expression. Platelet activation markers and inflammatory parameters were not correlated with each other at any time point after stroke.Conclusions— The initial increase in both CD62p and CD63 expression by platelets is followed by a differential regulation of both parameters after stroke. The rapid decrease in CD62p expression may be caused by shedding from the cell surface. Its persistent elevation makes CD63 a good candidate for studies on predictors for stroke recurrence. Our findings suggest that the expression of CD62p and CD63 by platelets is regulated independently from inflammatory indexes.
Stroke Risk After Posterior Circulation Stroke/Transient Ischemic Attack and its Relationship to Site of Vertebrobasilar Stenosis: Pooled Data Analysis From Prospective Studies
- Giosue Gulli,
- Lars Marquardt,
- Peter M. Rothwell and
- Hugh S. Markus
Stroke Volume 44, Issue 31 March 2013

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Background and Purpose—Recent prospective studies have shown vertebrobasilar (VB) stenosis predicts stroke risk in posterior circulation stroke and transient ischemic attack. It is unclear whether this association is independent of other risk factors, and whether intracranial or extracranial stenosis confers different risks.Methods—A pooled individual patient analysis of data from 2 prospective studies was performed in 359 patients presenting with VB transient ischemic attack or stroke. Contrast-enhanced magnetic resonance angiography, or computed tomography angiogram, and clinical follow-up were available in 323 patients. Risk of stroke was calculated from any VB transient ischemic attack/stroke in the month before the presenting episode (first event) and from the presenting event. A systematic review of similar prospective studies was performed.Results—Ninety-day risk of stroke from the first event was 24.6% in patients with VB stenosis versus 7.2% in those without (odds ratio, 4.2; 95% confidence interval, 2.1–8.6; P<0.0001). Risk was higher (33%) with intracranial (odds ratio, 6.5; 2.8–15.0; P<0.0001) than extracranial stenosis (16.2%; odds ratio, 2.5; 0.9–6.8; P=0.06). Risk from the presenting event was 9.6% in patients with stenosis versus 2.8% in those without (odds ratio, 3.7; 1.2–11.0; P=0.012), and again the risk was higher with intracranial stenosis. Cox regression showed the risk associated with VB stenosis was independent of other cardiovascular risk factors. The systematic review identified only 1 other report, which included only 6 patients.Conclusions—Symptomatic VB stenosis, particularly intracranial stenosis, is a strong independent predictor of stroke recurrence. The high early risk of stroke provides a strong rationale for randomized trials to determine whether stenting can reduce risk.
Dabigatran or Aspirin After Embolic Stroke of Undetermined Source in Patients With Patent Foramen Ovale: Results From RE-SPECT ESUS
- Hans-Christoph Diener,
- Aurauma Chutinet,
- J. Donald Easton,
- Christopher B. Granger,
- Eva Kleine,
- Lars Marquardt,
- Juliane Meyerhoff,
- Andrea Zini and
- Ralph L. Sacco
Stroke Volume 52, Issue 31 March 2021

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Background and Purpose:Patent foramen ovale (PFO) may increase the risk of embolic stroke of undetermined source (ESUS). Guidelines suggest anticoagulation may be more effective than antiplatelets in preventing stroke in patients with ESUS and PFO when interventional closure is not performed.Methods:Patients with ESUS randomized to dabigatran (150/110 mg BID) or aspirin (100 mg QD) from the RE-SPECT ESUS study (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) were included. The rate of recurrent stroke (primary end point) and ischemic stroke was reported for patients with and without baseline PFO. A meta-analysis comparing the effects of anticoagulant and antiplatelet therapy on ischemic stroke in patients with PFO was updated to include RE-SPECT ESUS.Results:PFO was present in 680 of 5388 (12.6%) patients with documented PFO status. The risk of recurrent stroke with dabigatran versus aspirin was similar in patients with and without PFO (P for interaction, 0.8290). In patients with PFO, the meta-analysis found no statistically significant difference between anticoagulant and antiplatelet therapy (odds ratio, 0.70 [95% CI, 0.43–1.14]) for ischemic stroke.Conclusions:There is insufficient evidence to recommend anticoagulation over antiplatelet therapy for patients with ESUS and a PFO. More data are needed to guide antithrombotic therapy in this population.Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02239120.
Abstract WMP107: Neuroimaging Characteristics of Intracranial Hemorrhages and Microhemorrhages in Infective Endocarditis
- Sung-Min Cho,
- Robert Marquardt,
- Lucy Zhang,
- Prateek Thatikunta,
- Ken Uchino and
- Dolora Wisco
Stroke Volume 48, Issue suppl_11 February 2017

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Introduction: Intracranial hemorrhage (ICH) is common in infective endocarditis (IE). We explored the imaging characteristics, predictors, and clinical implications of ICHs including intraparenchymal hemorrhage (IPH), and subarachnoid hemorrhage (SAH) and, subdural hematoma (SDH).Methods: We reviewed records of 116 consecutive acute IE patients by Duke’s criteria with neurological consultation or admission to stroke neurology service in a single tertiary referral center from January 2015 to July 2016. ICHs were defined as IPH, SAH, or SDH seen on CT. Microhemorrhages were identified on susceptibility weighted imaging (SWI) on MRI. Patient’s radiographic characteristics and complications were collected.Results: Of 116 patients, 25 persons (21.6%, median age 58) had ICHs, 14 with IPHs, 7 with SAHs, 3 with both IPH and SAH, and 1 SDH. Of 17 (14.7%) IPHs (median NIH Stroke Scale 6 and median volume 38.6cc), 10 (8.6%) IPHs were symptomatic and 7 IPHs were silent. Eleven persons (65%) with IPH also had ischemic strokes. Mycotic aneurysms were identified only in 1 (4.8%) in 21 persons with ICH who underwent cerebral angiogram. MRIs identified 66 persons with microhemorrhages (56.9%, median age 58.5) among 85 who underwent MRI. Eighteen (72%) of 25 persons with ICHs had microhemorrhages in SWI. In multivariate logistic regression analysis, ICH was associated with the presence of >5 microhemorrhages (odds ratio [OR]: 1.25, 95% confidence interval [CI]: 1.04-1.50) and staphylococcus aureus (OR: 1.25, 95% CI: 1.03-1.51). Ten persons (40%) with ICH died (7 with IPH and 4 with SAH) in the same hospitalization. Thirteen persons (52%) with ICH (median 21.4cc in 9 IPHs) underwent valve replacement at median of 13.5 days and 2 persons had new non-fatal strokes (1 IPH and 1 ischemic stroke).Conclusions: Intracranial macro- or micro-hemorrhages are seen in 73 (63%) persons with IE. The mortality of intracranial hemorrhage is high but the perioperative stroke risk appears low.
Abstract WMP35: The Characteristics of Infectious Intracranial Aneurysm and Indication of Cerebral Angiogram in Infective Endocarditis (IE)
- Sung-Min Cho,
- Robert Marquardt,
- Lucy Zhang,
- Prateek Thatikunta,
- Ken Uchino and
- Dolora Wisco
Stroke Volume 48, Issue suppl_11 February 2017

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Introduction: Infectious intracranial aneurysm (IIA) can complicate infective endocarditis (IE). We aim to describe the characteristics of IIA and to assess indications for cerebral angiography.Methods: We reviewed IIAs among 116 consecutive active IE by Duke’s criteria with neurological consultation or admission to stroke neurology service in a single tertiary referral center from January 2015 to July 2016. Susceptibility weighted imaging (SWI) hemorrhage was defined as low signal on SWI in sulci or parenchyma that was not apparent on CT.Results: Of 116 patients, 74 persons (63.8%, mean age of 54) underwent digital subtraction angiography (DSA). IIAs were identified in 13 (17.6%). All of 13 IIAs were unruptured and only one IIA had unrelated intracranial hemorrhage on CT. None of the IIA was seen with CTA or MRA. Eleven (85%) IIAs had clinical strokes (10 ischemic strokes, 1 intracerebral hemorrhage, median NIH stroke scale 3), and 2 neurologically asymptomatic with abnormal MRI. Six of 9 IIAs had SWI hemorrhage in sulci or parenchyma (5 in sulci, 5 in parenchyma, and 1 in both) and all of the lesions were in the vicinity of IIA. Contrast MRI was performed in 7 IIAs, and 4 IIAs had enhancements, all of which were present near the location of IIAs. Ischemic stroke, intracranial hemorrhage, intravenous drug abuse, and type of valve were not associated with the presence of IIA. Of 13 IIAs, 3 remained on antibiotic alone, 5 had antibiotic with coil embolization, and, 5 had antibiotic with glue embolization. Ten patients with IIAs had valvular surgery, including one person with untreated IIA. Out of all patients with IIA, only one intracerebral hemorrhage occurred as perioperative complication unrelated to treated IIA.Conclusions: IIAs were found in approximately one fifth of IE persons who underwent DSA. Imaging characteristics such as SWI hemorrhage in sulci or parenchyma and contrast enhancement appear to correlate with the presence of IIA. DSA should be performed when they are present.
Abstract WP16: Acute Stroke Treatment and Hemorrhagic Complication in Infective Endocarditis
- Prateek Thatikunta,
- Robert J Marquardt,
- Sung-Min Cho,
- Lucy Zhang,
- Ken Uchino and
- Dolora Wisco
Stroke Volume 48, Issue suppl_11 February 2017

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Introduction: Acute ischemic stroke (AIS) is common in patients with infective endocarditis (IE). Use of IV thrombolytic therapy (IV-tPA) has been reported and appears to carry greater risk of hemorrhage, while reports of endovascular therapy are rare. We present two cases where these interventions were utilized.Methods: A retrospective review was done of 116 consecutive patients with IE who were seen by stroke neurology in a tertiary care center from January 2015 to July 2016. Two cases were identified in which acute stroke therapy was utilized, one case with IV-tPA and one case with endovascular thrombectomy. We searched PubMed from inception to August 2016 and systematic review was performed to evaluate acute stroke therapy in IE.Results: In case 1, an 82 year old female with prosthetic aortic valve endocarditis and atrial fibrillation presented with slurred speech and right hemiplegia. IV-tPA was given within 2.5 hours, and NIHSS improved from 11 to 1 over 24 hours. CT Brain done 24 hours post-tPA revealed a small L thalamic hemorrhage. In case 2, a 49 year old IV drug-using male with prior IE and current prosthetic aortic valve endocarditis developed right middle cerebral artery occlusion with an NIHSS 17. Endovascular thrombectomy was performed with successful TICI 3 recanalization. CT Brain done 24 hours post-thrombectomy showed evolving right middle cerebral artery infarct with hemorrhagic conversion. Systematic review revealed 7 reports of IV thrombolysis, 5 reports of mechanical thrombectomy, and 3 reports with intra-arterial thrombolysis plus endovascular thrombectomy. Including our cases, IV thrombolysis alone had a hemorrhagic complication rate of 82% (9 out of 11 patients). Endovascular thrombectomy alone, all reporting at least TICI IIb recanalization, had a hemorrhagic complication rate of 17% (1 out of 6 patients). Intra-arterial thrombolysis and endovascular thrombectomy together had a hemorrhagic complication rate of 0% (0 out of 3 patients).Conclusion: Endovascular thrombectomy alone appears to be safer than IV-tPA alone in the management of AIS in patients with IE.
Abstract 2925: An inherited mutation of AKAP9 (Yotiao) causes Long QT Syndrome (LQTS)
- Lei Chen,
- Michelle L Marquardt,
- David J Tester,
- Kevin Sampson,
- Michael J Ackerman and
- Robert S Kass
Circulation Volume 116, Issue suppl_1616 October 2007

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A-Kinase Anchoring Protein 9 (AKAP9), or Yotiao, binds to the carboxy-terminus (C-T) of the IKs channel alpha subunit KCNQ1 and recruits cAMP-dependent protein kinase A (PKA) and protein phosphatase 1 (PP1) to the channel to control its phosphorylation state. Previously, an inherited LQT1-causing mutation in the KCNQ1 C-T/Yotiao binding domain was shown to disrupt the complex and render the channel functionally insensitive to cAMP-dependent regulation. Despite the critical role of Yotiao in mediating this fundamental physiological response, the large size of the Yotiao protein (over 200 kD) has hindered patient screens and, to date, no disease-linked mutations have been found in this adaptor protein. The objectives of the present study werefirst to locate reciprocal binding site(s) for KCNQ1 on Yotiao andto test whether mutation(s) in the binding module(s) might cause LQTS.Using GST fusion protein pull down and immunoprecipitation (IP) techniques, we identified two regions in Yotiao necessary for binding to KCNQ1: one within the Yotiao N-terminus (residues 29 – 46), and a second within its C-terminus (1574 –1643). Targeted sequence analysis was then carried out in fifty clinically diagnosed but genotype negative LQTS patients in the coding regions for these two KCNQ1 binding domains in AKAP9-encoded Yotiao. This analysis identified a novel missense mutation, S1570L-Yotiao, present in two siblings diagnosed with LQTS but absent in the normal population. We found that the S1570L mutation, located close to the Yotiao C-T binding motif for KCNQ1, disrupted the interaction between the two proteins and significantly reduced both basal and exogenous cAMP-induced KCNQ1 phosphorylation. Perforated patch experiments in CHO cells revealed that expression of S1570L-Yotiao significantly reduced basal IKS channel activity and completely ablated the response of the IKs channel to cAMP plus the phosphatase inhibitor okadaic acid. These reconstituted cellular consequences of the inherited S1570L-Yotiao mutation are consistent with delayed repolarization of the ventricular action potential observed in the affected siblings. Thus, we have demonstrated for the first time a link between an inherited AKAP mutation and human disease, LQTS.
Abstract TMP87: Early Surgery for Infective Endocarditis with Stroke Does Not Increase Post-operative Neurological Complications: What are We Waiting For?
- Lucy Q Zhang,
- Sung Cho,
- Robert Marquardt,
- Prateek Thatikunta,
- M. Shazam Hussain,
- Ken Uchino and
- Dolora Wisco
Stroke Volume 48, Issue suppl_11 February 2017

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Introduction: Ischemic and hemorrhagic stroke often complicate infective endocarditis (IE). Optimal timing of surgical intervention for IE with stroke remains controversial. We compared neurological outcomes of early and delayed valve surgery for IE complicated by stroke.Methods: We reviewed 73 patients with acute IE by Duke Criteria who underwent brain imaging (CT, MRI, or cerebral angiogram) before valve operations between December 2014 and August 2016. Date of IE diagnosis was defined as date of antibiotic initiation. Early surgery was defined as valve replacement ≤14 days from date of IE diagnosis and delayed surgery as >14 days. Neurological complication is defined as delirium >72 hours after extubation and cessation of sedation, new ischemic or hemorrhagic stroke.Results: Among 73 patients who underwent valve replacement surgery, 71 had evidence of stroke on imaging: 54 patients with acute or subacute ischemic infarct, 9 patients with evidence of intracerebral hemorrhage, and 8 patients with subarachnoid hemorrhage. The median time from IE diagnosis to surgery was 9 days. Forty patients had early surgery, and 33 patients had late surgery. Early surgery group had fewer patients with history of ischemic stroke (55% vs 79%, p=0.033), fewer acute or subacute infarcts on imaging (63% vs 88% p=0.016), but more native valve infections (73% vs 45%, p=0.018). The incidence of post-operative stroke was similar between both groups (2.5% vs 9%, p=0.32). In the delayed group, ischemic strokes occurred in 4 patients awaiting surgery. Hypertension and diabetes mellitus were associated with post-operative neurological complications (p<0.05), but pre-operative stroke on imaging was not.Conclusion: In IE patients with acute stroke, early surgery does not appear to increase post-operative neurological complications.
Abstract 232: Development and Validation of a Mathematical Model Representing Complex Cellular Interactions Within the Artery Wall: in Silico Approach to Test Targeted Interventions
- Marcella Torres,
- Jing Wang,
- Paul Yannie,
- Rebecca Segal,
- Angela Reynolds and
- Shobha Ghosh
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 38, Issue Suppl_11 May 2018

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Atherosclerotic cardiovascular diseases remain the number one cause of morbidity and mortality despite significant advances in lipid management. Complex cellular interactions occur within the artery wall requiring timely infiltration/egress of immune cells and lipoproteins within a changing inflammatory milieu that determine the progression of an atherosclerotic plaque. Lack of detailed understanding of the multiple processes involved and their potential interactions has hindered development of targeted therapies. The objective of this study was to develop a computational model of the sequential influx of immune cells in response to a trigger to permit a system-level analyses of the processes involved using ordinary differential equations (ODEs). Thioglycollate induced peritonitis was used as a model to examine the infiltration of immune cells and phenotypic polarization of macrophages in response to a stimulus. Peritoneal exudates obtained at 10 different time-points over 7 days were analyzed by FACS to determine the distribution of neutrophils, macrophages and Ly6C^Hi (M1) or Ly6C^Lo (M2) polarization. Weighted least squares of the different parameters were used to calibrate the model developed in our laboratory (Panel A) to simulate inflammation/repair during sepsis using the Levenberg-Marquardt algorithm. Panels B-D show the “match” of the experimental data to the calibrated model demonstrating the validity of this model. Since the ODEs are derived from a combination of known and hypothesized kinetics of the biological system, model the changes in physiological variables over time and are based on biological interactions, our calibrated mathematical model will permit the evaluation of changes in one or more targeted parameters in silico on immune cell distribution/phenotype. Efficacy of various macrophage-specific interventions (e.g., reduction in cholesterol content or inflammation) can be predicted prior to preclinical experimentation.
Abstract 17267: Contrast-Enhanced Magnetic Resonance Imaging Based T1-Mapping and Extracellular Volume Fractions are Associated With Peripheral Artery Disease
- Michael C Shieh,
- Tatiana Belousova,
- Addison A Taylor,
- Vijay Nambi,
- Joel D Morrisett,
- Christie M Ballantyne,
- Jean Bismuth,
- Dipan J Shah and
- Gerd Brunner
Circulation Volume 136, Issue suppl_114 November 2017

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Introduction: Extracellular volume fraction (ECV), measured with contrast-enhanced magnetic resonance imaging (CE-MRI), has been utilized to study myocardial fibrosis but its role in peripheral artery disease (PAD) remains unknown. We hypothesized that T1-mapping and ECV differ between PAD patients and matched-controls.Methods: A total of 37 individuals (18 PAD, 19 controls) underwent 3.0T CE-MRI at the mid-calf. T1-mapping was done before and after gadolinium contrast with a motion corrected Modified Look Locker Inversion Recovery (MOLLI) pulse sequence. T1 values were calculated with a 3-parameter Levenberg-Marquardt curve fitting algorithm. T1-maps were quantified in 5 calf muscle compartments (anterior [AM], lateral [LM], and deep posterior [DM] muscle groups; soleus [SM], and gastrocnemius [GM] muscles). Averaged peak blood pool T1 values were obtained from the posterior (PT) and anterior tibialis (AT); and peroneal artery (PE). PAD ECV was calculated for each muscle group as (1-hematocrit in %) · [ (1/T1m post) - (1/T1m pre) ] / [ (1/T1b post) - (1/T1b pre) ], where T1m is the peak T1 value of the respective muscle compartments and T1b the averaged peak arterial blood T1 value.Results:T1 values and ECV are heterogeneous across calf muscle compartments. Native peak T1 values of the AM, LM, and DM were significantly higher in PAD patients compared to controls (all p<0.028, Table). ECV of the AM and SM were significantly higher in PAD patients compared to controls (AM: 26.4% (21.2, 31.6) vs. 17.3% (10.2, 25.1), p=0.046; SM: 22.7% (19.5, 27.8) vs. 13.8% (10.2, 19.1), p=0.020). PAD patients with an ankle brachial index (ABI)<0.7 (n=6) compared with ABIs>=0.7 (n=12) had higher native peak T1 AM values (p=0.03).Conclusions: Native peak T1 values and ECV fractions of several calf muscle compartments are higher in PAD patients compared with matched-controls. These data suggest a potential utility of ECV to noninvasively determine skeletal muscle fibrosis in PAD.

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