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Moving Into the Neighborhood: Thinking Beyond Individuals to Improve Cardiovascular Health
- Brita Roy and
- Carley Riley
Circulation: Cardiovascular Quality and Outcomes Volume 7, Issue 41 July 2014

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Effects of External Electrical and Magnetic Fields on Pacemakers and Defibrillators: From Engineering Principles to Clinical Practice
- Roy Beinart and
- Saman Nazarian
Circulation Volume 128, Issue 251 December 2013

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Abstract 387: Role of Aldehyde Dehydrogenase (aldh) 2 in Angiotensin II-induced Decrease in Angiogenesis of Coronary Endothelial Cells
- Bipradas Roy and
- Suresh S Palaniyandi
Circulation Research Volume 127, Issue Suppl_131 July 2020

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Diabetes-induced coronary endothelial cell (CEC) dysfunction following defective angiogenesis is reported in cardiovascular diseases (CVD). Angiotensin II (Ang II), a vasoactive molecule, is upregulated in diabetes. However, the underlying molecular mechanisms of Ang II-induced CEC dysfunction are not fully understood. Aldehyde dehydrogenase (ALDH) 2 is cytoprotective in diabetic CVD. Thus, we hypothesize that ALDH2 improves Ang II-mediated defective CEC angiogenesis. To test our hypothesis, we treated the cultured mouse CECs with Ang II (0.1, 1 and 10 μM) for 2 and 4 hours. Next, we treated CEC with Alda-1 (10 μM), an ALDH2 activator or disulfiram (2.5 μM), an ALDH2 inhibitor, before challenging MCECs with Ang II. We found that Ang II attenuated tube formation (P<0.05 vs control) which indicates in vitro angiogenesis. Next, we found that Ang II have downregulated the mRNA expressions of vascular endothelial growth factor receptor VEGFR1 (p<0.05) and upregulated angiotensin II type-2 receptor (AT2R) (P<0.05) in cultured CECs compared to controls. ALDH2 inhibition with disulfiram potentiated Ang II-induced decrease in angiogenesis (P<0.005) by decreasing the expressions of VEGFR1 (P<0.0005) and increasing the expression of AT2R (p<0.05) relative to Ang II alone. Additionally, activation of ALDH2 activity with Alda-1 rescued Ang II-induced decrease in angiogenesis (P<0.05) by increasing the expression of VEGFR1 (P<0.05) and decreasing the expression of AT2R (P<0.05) relative to Ang II alone. Finally, we conclude that ALDH2 can be an important therapeutic target to improve coronary angiogenesis in diabetic CVD.
Abstract P429: Aldehyde Dehydrogenase 2 Regulates Angiogenesis Of Coronary Microvascular Endothelial Cells Via A Novel Signaling Pathway
- Bipradas Roy,
- Guodong Pan and
- Suresh Palaniyandi
Circulation Research Volume 129, Issue Suppl_13 September 2021

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Coronary microvascular endothelial cell (CMECs) damage is implicated in diabetes-mediated heart failure with preserved ejection fraction (HFpEF). 4-hydroxy-2-nonenal (4HNE), a reactive aldehyde that is increased in diabetic heart, decreases angiogenesis in cultured mouse CMECs by decreasing the mRNA and protein levels of vascular endothelial growth factor receptor (VEGFR)2. Nuclear factor-kappa B (NF-kB), a transcription factor, was shown to transcribe VEGFR2. Thus, we presume 4HNE modulates NF-kB-mediated VEGFR2 transcription and regulates angiogenesis in CMECs. Aldehyde dehydrogenase (ALDH) 2, a mitochondrial enzyme that detoxifies 4HNE and confers cryoprotection. However, ALDH2 activity was reduced in the diabetic hearts which results in the augmentation of 4HNE-induced cardiotoxicity. Thus, we hypothesize that ALDH2 in CMECs reduces 4HNE-mediated cell signaling aberrations, and thereby, preserves coronary angiogenesis. We treated the cultured mouse CMECs with disulfiram (DSF) (2.5 μM), an ALDH2 inhibitor, alda1 (10 μM), an ALDH2 activator and prostratin (1 μM), an NF-κB activator prior to challenging the CMECs with 4HNE (75 μM). Our tube-formation angiogenesis assay revealed that pretreatment with DSF exacerbated a 4HNE-induced decrease in CMECs angiogenesis (P<0.0005 vs con and P<0.05 vs both 4HNE & DSF alone) while pretreatments with alda1 and prostratin attenuated a 4HNE-induced decrease in CMEC angiogenesis (P<0.05 vs 4HNE alone). DSF pretreatment exacerbated 4HNE mediated decrease in ALDH2 (P<0.005 vs con), phospho-IKBα (P<0.0005 vs con and P<0.05 vs both 4HNE and DSF alone), NF-κB levels, and nuclear translocation (P<0.0005 vs con and P<0.05 vs both 4HNE & DSF alone) and VEGFR2 (P<0.0005 vs con and P<0.05 vs both 4HNE and DSF alone) levels in cultured CMECs. Pretreatment with both prostratin and alda1 increased ALDH2 (P<0.0005 vs con), VEGFR2 (P<0.05 vs con) and NF-κB (P<0.005 vs con) levels in CMECs. The cardiac tissue samples of db/db mice when they manifest HFpEF showed increased 4HNE adducts, decreased NF-kB and VEGFR2 levels in CD31+ CMECs besides exhibiting low CMEC density. In conclusion, ALDH2 attenuates 4HNE-mediated decrease in coronary angiogenesis by decreasing VEGFR2 levels via low NF-κB mediated transcription.
Echo-Doppler Hemodynamics: An Important Management Tool for Today’s Heart Failure Care
- Roy Beigel,
- Bojan Cercek,
- Robert J. Siegel and
- Michele A. Hamilton
Circulation Volume 131, Issue 1117 March 2015

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Abstract P3017: Aldehyde Dehydrogenase 2 Augments Adiponectin Signaling In Coronary Angiogenesis In Hfpef Associated With Diabetes
Circulation Research Volume 131, Issue Suppl_15 August 2022

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4-hydroxy-2-nonenal (4HNE), a reactive aldehyde, is elevated in diabetes that decreases coronary angiogenesis and this was rescued by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme that detoxifies 4HNE. Adiponectin (APN), a pleiotropic hormone, has pro-angiogenic properties which was shown to be critical in diabetes and its complications. However, the interaction between ALDH2 and APN signaling in coronary angiogenesis is unknown. Coronary endothelial cell (CEC) damage is the initiating step of diabetes-mediated heart failure with preserved ejection fraction (HFpEF) pathogenesis. Thus, we hypothesize that ALDH2 restores 4HNE-induced downregulation of APN signaling in CECs and subsequent coronary angiogenesis in diabetic HFpEF. First of all, APN significantly increased coronary angiogenesis. However, 4HNE treatment significantly decreased the levels of APN signaling molecules including adiponectin receptor (AdipoR)1, APPL1, phospho-AMPK, AMPK, phospho-AKT, and AKT in mouse CECs. Treatment with disulfiram (DSF), an ALDH2 inhibitor, exacerbated 4HNE-mediated decreases in APN-induced increased coronary angiogenesis and APN-signaling cascades, whereas pretreatment with alda1, an ALDH2 activator, rescued the effect of 4HNE. We employed control (db/m) mice, spontaneous type-2 diabetic (db/db) mice, ALDH2*2 knock-in mutant mice with intrinsic low ALDH2 activity (AL), and diabetic mice with intrinsic low ALDH2 activity (AF) that were created by crossing db/db and AL mice to test our hypothesis in vivo. AF mice exhibit severe HFpEF at 6 months compared to age-matched db/db mice as well as 3 months-old AF mice. At 6m, db/db, AL & AF mice significantly decreased APN response to coronary angiogenesis along with increased serum APN levels and decreased cardiac tissue levels of AdipoR1, APPL1, P-AMPK, and P-AKT implicating occurrence of APN resistance which was higher in AF mice. Alda-1 treatment improved APN-mediated angiogenesis significantly in db/db and AF mice. In conclusion, 4HNE-induces APN resistance and subsequently decreases coronary angiogenesis in diabetic HFpEF which was rescued by ALDH2 activation.
Abstract P105: Women with Atrial Fibrillation have Increased Risk of Incident Stroke: Insights from a Propensity-Matched Study of the AFFIRM Trial
- Brita Roy,
- Ravi V Desai,
- Mustafa I Ahmed,
- Gregg C Fonarow,
- Wilbert S Anorow and
- Ali Ahmed
Circulation Volume 125, Issue suppl_1013 March 2012

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Background: Women with atrial fibrillation (AF) have been reported to have poor outcomes. It remains unclear if this association is intrinsic or mediated by the higher comorbidity burden of female AF patients. Therefore, we examined the association between sex and outcomes in a balanced cohort of propensity-matched AF patients who participated in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial.Methods: Of the 4060 AFFIRM patients, 1594 (39%) were women. Propensity scores for female sex were calculated for each of the 4060 patients, and were used to assemble a cohort of 1097 pairs of men and women who were balanced on 51 baseline characteristics, including major cardiovascular (CV) risk factors and medication use, including warfarin. Matched Cox regression models were used to estimate the association between female sex and outcomes during 6 years of follow-up.Results: Patients (n=4060) had a mean (±SD) age of 70 (±8) years and 13% were African American. All-cause mortality occurred in 19% and 15% of matched men and women, respectively (matched HR when women were compared to men, 0.88; 95% CI, 0.69-1.11; p=0.279). All-cause hospitalization occurred in 61% of both men and women (matched HR for women, 1.06; 95% CI, 0.93-1.21; p=0.372). Sex was not associated with CV hospitalization (matched HR for women, 1.13; 95% CI, 0.97-1.32; p=0.111). Ischemic stroke occurred in 3% and 5% of matched men and women, respectively (OR when women were compared to men, 2.02; 95% CI, 1.28-3.18; p=0.002). There was no sex-related difference in major bleeding (7% each).Conclusion: In a cohort of AF patient in which men and women were well-balanced on 51 baseline characteristics including warfarin use, women had increased risk of stroke, but there was no sex-related variation in all-cause mortality or CV hospitalization.
Abstract 15488: Cardiac Magnetic Resonance T1 Mapping of Left Atrial Myocardium
- Roy Beinart,
- Irfan M Khurram,
- Hirad Yarmohammadi,
- Henry R Halperin,
- Hugh Calkins,
- Stefan L Zimmerman and
- Saman Nazarian
Circulation Volume 126, Issue suppl_2120 November 2012

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Introduction: Magnetic resonance imaging (MRI) T1 mapping is an emerging tool for objective assessment of myocardial fibrosis.Hypothesis: T1 mapping for left atrial (LA) myocardium in patients with atrial fibrillation (AF) is feasible.Methods: MRI (1.5 Tesla) was performed in 51 consecutive patients (64% males, median age 55 years, inter-quartile range (IQR) 51-65 years) prior to AF ablation (53% prior to first ablation, 47% prior to repeat ablation) and in 16 healthy volunteers (31% males, median age 26 years, IQR 23-30 years). Vertical long-axis planes were acquired using the Modified Look-Locker Inversion-recovery (MOLLI) sequence. T1 measurements were obtained from regions of interest placed on the posterior wall of the left atrium using Mass Research software (Medis, The Netherlands). Intra-cardiac point-by-point bipolar LA voltage maps were acquired at the beginning of ablation procedures using CARTO 3D electroanatomic mapping system (Biosense Webster).Results: The median LA T1 relaxation time was shorter in patients with AF (387 ms, IQR 364-428 ms) compared to healthy volunteers (459 ms, IQR 418-532 ms, P<0.001) [Figure] and was shorter in AF patients with history of ablation compared to patients without prior ablation (P=0.035). Each 100 ms increase in T1 relaxation time was associated with 0.1 mV increase in intra-cardiac bipolar LA voltage after adjustment for age, prior ablation, type of AF, hypertension and diabetes in a generalized estimating equations model clustered by subject (P=0.019).Conclusion: MRI T1 mapping of the LA myocardium is feasible and may improve the quantification of fibrotic changes in LA myocardium. Shorter average T1 times, indicating increased fibrosis, were observed with prior ablation attempts as a preliminary validation tool for this assay.
Hemodynamic Consequences of Oxygen Breathing in Left Ventricular Failure
- WALTER J. DALY and
- ROY H. BEHNKE
Circulation Volume 27, Issue 21 February 1963

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As in normal men, oxygen breathing in patients with left ventricular failure is associated with a further reduction of cardiac index, partially the result of decreased stroke index and partially the result of decreased heart rate. The decrease in heart rate and cardiac index is associated with a decrease in left ventricular work index without impairing the delivery of oxygen to the tissues or the over-all tissue pO₂. In this group of patients, oxygen breathing did not result in a decreased pulmonary vascular resistance.
Abstract P503: Aldehyde Dehydrogenase 2 Activator 1 Potentiates The Effects Of Empagliflozin, A Sodium-glucose Cotransporter 2 Inhibitor, In Diabetes-mediated Heart Failure With Preserved Ejection Fraction
- Guodong Pan,
- Bipradas Roy and
- Suresh Palaniyandi
Circulation Research Volume 129, Issue Suppl_13 September 2021

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4-hydroxy-2-nonenal (4HNE), a cellular reactive aldehyde which is significantly increased in diabetic hearts due to decrease in the activity of its metabolizing enzyme, aldehyde dehydrogenase (ALDH)2, contributes to diabetes mellitus (DM)-mediated cardiotoxicity. Therefore, we hypothesize that lowering 4HNE ameliorates heart failure with preserved ejection fraction (HFpEF) in DM. To ameliorate DM mediated HFpEF, we will lower diabetes-mediated oxidative stress-induced 4HNE accumulation as well as augment 4HNE detoxification by activating ALDH2, via pharmacological agents. We induced type-2 DM by feeding high-fat diet (HFD) in ALDH2*2 mutant mice which have intrinsically low ALDH2 activity and thus having increased cardiac 4HNE levels. After 4 months of DM, the mice exhibited features of HFpEF and we treated the diabetic ALDH2*2 mice with vehicle (Veh), empagliflozin (EMP) (3mg/kg/d), a sodium-glucose cotransporter (SGLT) 2 inhibitor to reduce hyperglycemia and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as combination of EMP + Alda-1 (E + A), via subcutaneous osmatic pumps. After treating for 2 months, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved running distance (RD, 231 ± 53 m), ejection fraction after running (EF, 69 ± 5 %), and decreased left atrial area (LA, 3.0 ± 0.2 mm²), cardiomyocyte cross-section area (CA, 251 ± 32 μm²) and myocardial fibrotic area (FA 1.0 ± 0.3 %) in ALDH2*2 mice with diabetic HFpEF compared to EMP (RD 142 ± 53 m; EF 62 ± 5 %; LA 3.5 ± 0.3 mm²; CA 303 ± 55 μm² ; and FA 3.2 ± 1.8 %), Alda-1 (RD 183 ± 73 m; EF 68 ± 3 %; LA 3.2 ± 0.2 mm²; CA 288 ± 34 μm² ; and FA 2.5 ± 1.2 %) and Veh (RD 52 ± 66 m; EF 55 ± 5.0 %; LA 4.7 ± 0.4 mm²; CA 448 ± 65 μm² ; and FA 11 ± 3.5 %). This improvement was exerted by decreasing 4HNE levels as well as attenuating 4HNE-mediated decrease in cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. In conclusion, our data implicate that ALDH2 activation along with the treatment of hypoglycemic agents may be important strategy to alleviate diabetic HFpEF.
Abstract 17834: Incident Cardioversion is Associated with Reduced Mortality among Older Adults with Atrial Fibrillation: Insights from the AFFIRM Trial
- Brita Roy,
- Ravi V Desai,
- Susan J Zieman,
- Mustafa I Ahmed,
- Gregg C Fonarow,
- Wilbert S Aronow and
- Ali Ahmed
Circulation Volume 122, Issue suppl_2123 November 2010

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Background: A rhythm control strategy has not been shown to improve long-term outcomes in atrial fibrillation (AF), possibly due to detrimental effects of antiarrhythmic medications. Aging is associated with impaired left ventricular early relaxation, thus, diastolic filling depends more on atrial contraction, impaired in AF. Electrical cardioversion (EC) is an alternate way to restore normal sinus rhythm, but is often underused in older adults due to concern for its invasive nature and risk of stroke, and lack of evidence for long-term benefit. We explored the hypothesis that the use of EC would be associated with reduced mortality in older adults with AF.Methods: In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 4060 patients with AF were randomized to rate versus rhythm control strategy. Of these, 3091 (76%) patients were ≥65 years. EC was a rhythm control strategy, and 47% of patients in the rhythm-control group received EC. However, 36% of the rate-control patients also received EC. We used multivariable Cox regression models, adjusting for baseline demographics and other covariates including randomization factor, to estimate the association between incident EC and outcomes during 6 years of follow-up.Results: Patients (n=3091) had a mean (±SD) age of 73 (±4) years, 43% were women and 9% African American. EC was associated with significant reduction in all-cause mortality among elderly AF patients (adjusted HR when EC was compared with no-EC, 0.71; 95% CI, 0.58–0.87; p=0.001). In contrast, among younger adults, EC was not associated with mortality (adjusted HR when EC was compared with no-EC, 1.46; 95% CI, 0.89–2.39; p=0.138). This age-related difference in the association between EC and mortality was statistically significant (adjusted p for interaction, 0.016).Conclusions: Older adults with AF receiving incident electrical cardioversion had lower risk of death. These findings are intriguing and mechanistically plausible, but need to be tested prospectively.
Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic‐Reperfusion Injury Due to 4‐Hydroxy‐2‐Nonenal Induced Coronary Endothelial Cell Damage
- Guodong Pan,
- Bipradas Roy and
- Suresh Selvaraj Palaniyandi
Journal of the American Heart Association Volume 10, Issue 1821 September 2021

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BackgroundAldehyde dehydrogenase‐2 (ALDH2), a mitochondrial enzyme, detoxifies reactive aldehydes such as 4‐hydroxy‐2‐nonenal (4HNE). A highly prevalent E487K mutation in ALDH2 (ALDH2*2) in East Asian people with intrinsic low ALDH2 activity is implicated in diabetic complications. 4HNE‐induced cardiomyocyte dysfunction was studied in diabetic cardiac damage; however, coronary endothelial cell (CEC) injury in myocardial ischemia‐reperfusion injury (IRI) in diabetic mice has not been studied. Therefore, we hypothesize that the lack of ALDH2 activity exacerbates 4HNE‐induced CEC dysfunction which leads to cardiac damage in ALDH2*2 mutant diabetic mice subjected to myocardial IRI.Methods and ResultsThree weeks after diabetes mellitus (DM) induction, hearts were subjected to IRI either in vivo via left anterior descending artery occlusion and release or ex vivo IRI by using the Langendorff system. The cardiac performance was assessed by conscious echocardiography in mice or by inserting a balloon catheter in the left ventricle in the ex vivo model. Just 3 weeks of DM led to an increase in cardiac 4HNE protein adducts and, cardiac dysfunction, and a decrease in the number of CECs along with reduced myocardial ALDH2 activity in ALDH2*2 mutant diabetic mice compared with their wild‐type counterparts. Systemic pretreatment with Alda‐1 (10 mg/kg per day), an activator of both ALDH2 and ALDH2*2, led to a reduction in myocardial infarct size and dysfunction, and coronary perfusion pressure upon cardiac IRI by increasing CEC population and coronary arteriole opening.ConclusionsLow ALDH2 activity exacerbates 4HNE‐mediated CEC injury and thereby cardiac dysfunction in diabetic mouse hearts subjected to IRI, which can be reversed by ALDH2 activation.
Magnetic Resonance Imaging and Implantable Devices
- Saman Nazarian,
- Roy Beinart and
- Henry R. Halperin
Circulation: Arrhythmia and Electrophysiology Volume 6, Issue 21 April 2013

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Abstract 2864: Regional Differences in Left Atrial Wall Thickness in Patients With Atrial Fibrillation
- Roy Beinart,
- Kevin Heist,
- Sheldon Singh,
- Rajesh Kabra,
- Dan Blendea,
- David Donaldson,
- Jacob Koruth,
- Conor Barrett,
- Jeremy Ruskin and
- Moussa Mansour
Circulation Volume 120, Issue suppl_183 November 2009

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Introduction: Successful catheter ablation of atrial fibrillation (AF) requires the creation of transmural lesions in the left atrium (LA). LA wall thickness is thus relevant both for procedural efficacy (the creation of transmural lesions in thick regions) and safety (prevention of perforation in thin regions). This study sought to evaluate regional LA wall thickness in patients with AF.Methods: LA muscular wall thickness (excluding fat) was measured by 64 slice cardiac computed tomography (CT) in 60 patients with persistent AF prior to catheter ablation procedures. Measurements were performed in all patients at 11 distinct LA locations, including 3 at the roof (right, middle left), 3 at the floor (right, middle, left), 4 at the posterior wall (right, middle, middle-superior, left) and 1 at the origin of the mitral isthmus.Results: There was a large range of LA wall thickness (average thickness 1.87±0.37 mm, range 0.7–3.3 mm). There was no significant correlation between overall LA size and average wall thickness. There were significant regional differences in LA wall thickness, however (figure). In particular, the LA roof was significantly thicker than the posterior wall and floor (p<0.001), and the mitral isthmus was also significantly thicker than the posterior wall (p<0.001) and floor (p<0.001).Conclusions: In patients with persistent AF, there is inter- and intra-patient variability in the thickness of the LA muscular wall. In most patients however, the roof and mitral isthmus are thicker compared to the posterior wall and floor.
Complete Transposition of the Great Vessels : Unusual Longevity in a Case with Subpulmonary Stenosis
- LAURENCE P. STERNS,
- ROY M. BAKER and
- JESSE E. EDWARDS
Circulation Volume 29, Issue 41 April 1964

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A case of survival to the age of 11 years is reported in a patient with complete transposition of the great vessels. Additional malformations in the form of subpulmonary stenosis, ventricular septal defect, and patent ductcus arteriosus may have contributed to the unusually long period of survival. Surgical creation of an atrial septal defect and of a subclavian-pulmonary arterial anastomosis when the patient was 3 years old may have augmented the beneficial effects of the existing associated malformations.
Abstract P3027: Intermittent Fasting Improves High Fat Diet Mediated Heart Failure With Preserved Ejection Fraction
- Guodong Pan,
- Bipradas Roy,
- Ramandeep Rattan and
- Suresh S Palaniyandi
Circulation Research Volume 131, Issue Suppl_15 August 2022

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Intermittent fasting (IF) has improved metabolic aberrations in metabolic diseases, however, the mechanism is unclear. Our lab focuses on 4-hydroxy-2-nonenal (4HNE), an oxidative stress byproduct which accumulates in metabolic diseases, in cardiac damage and activity of aldehyde dehydrogenase 2 (ALDH2), a 4HNE detoxifying enzyme, which was implicated in cardioprotection. We reported that the ALDH2*2 knock-in mutant mice (AL) with low intrinsic ALDH2 activity that were fed with high-fat diet (HFD) exhibited severe heart failure with preserved ejection fraction (HFpEF) compared to HFD fed control mice (C57). We hypothesized that IF can contribute to the improvement of HFpEF even in AL mice by reducing 4HNE. C57 and AL mice that were fed HFD and L-NAME (nitric oxide inhibitor) in drinking water were grouped as C57-free and AL-free meaning taking food freely or C57-IF and AL-IF meaning daily 16 hours fasting with 8-hr free access to food. After 2-months of HFD feeding, the body weights of C57-IF (35.5±3.8g) and AL-IF (36.7±3.4g) groups were significantly lower than C57-free (43.5±4.2g, p<0.05 vs C57-IF) and AL-free (45.8±5.6g, p<0.05 vs AL-IF) groups. The 24-hour food intakes of C57-IF (8.6±0.9 KCal) and AL-IF (8.8±1.1 KCal) were significantly decreased, compared to C57-free (12.3±1.7 KCal, p<0.05 vs C57-IF) and AL-free (13.3±1.5 KCal, p<0.05 vs AL-IF) groups. The respiratory exchange ratio (RER) of AL-free group (0.62±0.12) was significantly lower than three other groups (p<0.05 vs C57-free, C57-IF and AL-IF, respectively). The E/A ratio (E/A), a diastolic parameter, was decreased in C57-free (1.14±0.21) and AL-free (0.89±0.17) groups, not in C57-IF (2.15±0.31, p<0.05 vs C57-free) and AL-IF (1.97±0.25, p<0.05 vs AL-free) groups. The E/A in AL-free group was also lower than C57-free group (p<0.05). Another diastolic parameter, isovolumic relaxation time (IVRT) was also prolonged in C57-free (27.3±3.3 ms) and AL-free (29.4±3.7 ms) mice, not in C57-IF (13.3±1.8 ms, p<0.05 vs C57-free) and AL-IF (15.2±2.1 ms, p<0.5 vs AL-free) mice. In conclusion, IF decreased food intake and obesity, and improved metabolism and heart function in both C57 and ALDH2*2 mice with HFpEF, and also diminished the differences in RER and E/A between them via lowering the 4HNE adducts.
Some of the People, Some of the Time: Susceptibility to Acute Rheumatic Fever
- Penelope A. Bryant,
- Roy Robins-Browne,
- Jonathan R. Carapetis and
- Nigel Curtis
Circulation Volume 119, Issue 510 February 2009

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Acute rheumatic fever is a major cause of heart disease in large parts of the world, but it remains unknown why only a small fraction of those who are infected with rheumatogenic group A streptococci develop an abnormal immune response that leads to acute rheumatic fever. An understanding of the mechanisms underlying host susceptibility can provide important insights into pathogenesis that in turn can inform new treatments. Extensive searches for susceptibility factors have been undertaken, including human leukocyte antigens, B-cell alloantigens, and cytokine genes. Although significant associations have been found between genetic factors and acute rheumatic fever, study results often conflict with each other. This review explores current understanding about host susceptibility to acute rheumatic fever and provides an overall perspective to the number of studies that have recently addressed this subject.
Abstract 13037: Self-Care Questionnaire Detects More Brain Injury in Comparison to Cognitive Screener in Heart Failure
- Mary A Woo,
- Bhaswati Roy,
- Gregg C Fonarow and
- Rajesh Kumar
Circulation Volume 134, Issue suppl_111 November 2016

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Introduction: Heart failure (HF) patients often have poor self-care (SC) and cognitive deficits. Both factors are closely related and require brain control of important skill sets. However, it is unclear if SC or cognition are linked to injury in different brain regions or if SC vs. cognition evaluation differs in the detection of brain damage amounts.Hypothesis: To determine if a measure of SC or cognition detects more brain injury in HF.Methods: Brain diffusion Tensor Imaging (DTI) data were collected from 10 HF (age 56.8±8.1 years; 8 male; LVEF 26.4±11.9% NYHA class II/III) using a 3 Tesla MRI scanner, Self-care was examined with the Self-Care of Heart Failure Inventory (SCHFI), and cognition with the Montreal Cognitive Assessment (MoCA) test. Using DTI data, mean diffusivity (MD; higher values=brain injury) maps were used to examine associations between SCHFI (maintenance and confidence subscales) and MoCA in HF subjects using partial correlation procedures (covariates: age and gender; uncorrected threshold p<0.005).Results: Significant negative correlations between MD and confidence scores emerged in the prefrontal cortex. hippocampus, amygdala, anterior and posterior cingulate, anterior corpus callosum, mid and posterior thalamus, posterior insula, putamen, inferior temporal lobe, and cerebral vermis, and between MD and maintenance scores in the right putamen, external and internal capsule, and right inferior temporal lobe (Figure). Significant negative correlations were observed between MD and MoCA scores in the prefrontal cortex, occipital cortex, cerebellum, and mid-inferior temporal lobe (Figure).Conclusions: HF subjects show more wide-spread and significant correlations between regional MD values/brain injury and SCHFI scores compared to MoCA values. The findings suggest that damage in cognitive and decision-making control sites better correlate with SCHFI over MoCA scores.
Abstract 15261: Aberrant Insular-Prefrontal Cortex Fiber Connectivity in Patients With Heart Failure
- Mary A Woo,
- Bhaswati Roy,
- Gregg C Fonarow and
- Rajesh Kumar
Circulation Volume 136, Issue suppl_114 November 2017

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Heart failure (HF) patients often show high rates of depressive symptoms and cognitive deficits, which are linked to increased mortality and poor quality of life. Insula and prefrontal cortices, brain areas which are involved in mood and cognition, show significant changes in HF. However, it is unknown if fiber connectivity between these 2 brain regions is impaired, and thus could exacerbate these symptoms, in HF. Therefore, the specific aim of this study was to determine fiber characteristics, including mean fiber counts and tract lengths connecting insular lobes to prefrontal cortices, using diffusion tensor imaging (DTI)-based fiber tractography procedures.Methods: Brain DTI data were collected from 17 HF (age 54.1±9.0 yrs; 13 male; LVEF 30.8±10.9%; NYHA class II/III) and 17 healthy controls (age 51.9±4.5 yrs; 13 male) using a 3.0 Tesla MRI scanner. Whole-brain fiber tracts generated from DTI data and region-of-interest analyses were performed to examine insular-prefrontal cortices connecting fiber tract integrity (mean fiber counts and length) using Trackvis software. Fiber characteristics were compared between HF and controls using ANCOVA (covariates: age and gender).Results: Average fiber tracts connecting right insular to right prefrontal cortex were reduced in HF (HF vs. controls: 30±24 vs. 55±32; p=0.02), as well as mean fiber length were shorter in HF (HF vs. controls: 73±19.9mm vs. 88.7±19.9mm; p=0.03) compared to controls.Conclusions: Diminished fiber connectivity between insular and prefrontal cortices might be related to loss of neurons and glial cells secondary to hypoxic/ischemic processes. These findings suggest that aberrant fiber connections between insula and prefrontal areas may contribute to mood and cognitive dysfunctions and thus, deterioration in survival and quality of life in the condition.
Abstract 12431: White Matter Brain Injury Increased in Heart Failure Subjects With Obstructive Sleep Apnea
- Mary A Woo,
- Bhaswati Roy,
- Gregg C Fonarow and
- Rajesh Kumar
Circulation Volume 138, Issue Suppl_16 November 2018

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Heart failure (HF) patients have a high incidence of obstructive sleep apnea (OSA), which has been linked to grey matter damage in brain areas that control breathing, including cerebellar climbing, cerebellar pontine, medulla, and pons regions. However, the status of white matter (WM) areas which communicate between these grey matter areas in HF, and which could exacerbate OSA, is unclear. Therefore, our aim was to examine WM tissue integrity of breathing control sites in HF subjects with OSA compared to non-OSA HF and controls using diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures via brain magnetic resonance imaging.Methods: Brain DTI data were collected from 6 HF with OSA (age 56.2±4.8 yrs; 4 male; LVEF 31.2±8.6%; NYHA class II/III; AHI, 28.4±20.2 events/hour), 6 HF without OSA (age 58.3±8.8 yrs; 5 male; LVEF 29.0±13.9%; NYHA class II/III), and 4 healthy controls (age 55.3±1.3 yrs; 3 male) using a 3.0-Tesla MRI scanner. MD maps were calculated from DTI data, normalized to a common space, and smoothed. The smoothed MD maps were used to examine WM integrity in HF with OSA vs controls and HF without OSA vs controls (SPM12; ANCOVA; covariates, age and gender; p<0.005).Results: Brain damage appeared in WM regions, with significantly increased MD values (indicative of chronic tissue injury) in HF with OSA over HF without OSA and control subjects. WM regions that link breathing control regions, including sites within the cerebellar pontine (Fig 1a), cerebellar climbing (Fig 1c), medulla, and pons (Fig 1b) showed extensive damage in HF with OSA over controls as compared to HF without OSA over controls.Conclusions: HF subjects with OSA show exaggerated brain injury in WM areas that are involved in breathing control. The brain damage specific to these WM regions may contribute to deficient respiratory regulations found in the condition and may exaggerate the adverse risks and effects of OSA on morbidity and mortality in HF.

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