bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4167: Prognostic Importance of Nutritional Status in Patients with Chronic Heart Failure
Authors: Shiba Nobuyuki , Tada Tomohiro , Matsuki Mika , Kagaya Yutaka , Shimokawa Hiroaki
Published: April 2024

Background:
Nutritional abnormalities are common among patients with chronic heart failure (CHF). However, little is known regarding clinical implication to evaluate the nutritional status in CHF patients. In this study, we examined the prognostic impact of nutrition-related factors, including serum albumin level (ALB), total lymphocyte count (TLC), and body mass index (BMI) in patients with CHF.

Methods:
We prospectively enrolled 280 stable patients with stage-C/D CHF since February 2000. Kaplan-Meier analyses and multivariate Cox regression analyses were performed to evaluate the association between the mortality and the nutrition-related factors mentioned above. Covariables used in the multivariate models were ALB, TLC, BMI, hemoglobin concentration, left ventricular ejection fraction, etiology of CHF, serum creatinine level, and age at the entry.

Results:
The mean age of the study population was 61.2±14.9 years and the mean follow-up period was 2.4±1.5 years. Kaplan-Meier analyses showed that the incidences of all-cause mortality were significantly higher in patients with lower ALB, lower TLC, or lower BMI as compared those without the nutritional abnormalities (Figure

). Multivariate analyses revealed that higher TLC was an independent significant predictor of freedom from cardiac-cause death (HR 0.9993, p=0.016) and higher ALB was significantly associated with increased survival (HR 0.563, p=0.03).

Conclusions:
The evaluation of nutritional status may be a powerful and cost-effective tool in predicting the mortality of patients with CHF. Further research is necessary to evaluate the importance of nutritional improvement in such patients.
Abstract 4178: Cardiovascular Event-Free Survival in Post-Menopausal Women with Polycystic Ovary Syndrome: Results from the Women’s Ischemia Syndrome Evaluation
Authors: Shaw Leslee J , Azziz Ricardo , Stanczyk Frank Z , Sopko George , Braunstein Glenn D , Dehoff Rhonda M , Handberg Eileen M , Berga Sarah , Johnson B. Delia , Bittner Vera , Rogers William , Pepine Carl J , Merz C. Noel Bairey
Published: April 2024

Background:
Women with polycystic ovary syndrome (PCOS) have a greater frequency and clustering of cardiac risk factors. Despite this, the link between PCOS and cardiovascular disease has not been established.

Objective:
This study’s aim was to evaluate cardiovascular (CV) prognosis in women with biochemical and clinical evidence of PCOS in 390 post-menopausal women (not taking exogenous hormone therapy) prospectively enrolled in the NIH-NHLBI sponsored Women’s Ischemia Syndrome Evaluation (WISE).

Methods:
PCOS (n=104) was defined by a premenopausal history of irregular menses accompanied by biochemical evidence of hyperandrogenemia. Hyperandrogenemia was defined as the top quartile of either androstenedione ≥701 pg/ml], testosterone (T; ≥30.9 ng/dl), free T (≥4.5 pg/ml), or androgen index (free T /sex hormone binding globulin [SHBG] ≥9.9], or lowest quartile of SHBG (≥30.8 nmol/l). Univariable and multivariable Cox proportional hazard model was used to estimate CV death (CVD) or myocardial infarction (MI) (n=52).

Results:
Women with evidence of hyperandrogenemia were more often diabetic (p<0.0001), obese (p=0.005), had the metabolic syndrome (p<0.0001), and experienced menopause at a younger age (p=0.026). Women meeting criteria for PCOS had a 2.6-fold (95% CI=1.5– 4.5) higher risk of CVD or MI (p<0.0001) (see Figure

). This relationship was maintained in a risk-adjusted model controlling for diabetes, hypertension, and angiographic coronary disease severity (p=0.001).

Conclusion:
Among post-menopausal women undergoing coronary angiography for suspected ischemia, PCOS is associated with worsening cardiovascular event-free survival.
Abstract 4188: Tumor Necrosis Factor-Alpha Regulates Adipose Tissue Macrophage Recruitment and CCR2 Expression
Authors: Bodary Peter , Denstaedt Scott , Wickenheiser Kevin , Shen Yuechun , Sharp Sarah , Ohman Minna , Eitzman Daniel
Published: April 2024

Factors regulating adipose tissue macrophage recruitment are largely unknown. Since tnf-alpha may promote diabetes in obesity, we hypothesized that tnf-alpha may be an important mediator of both adipose tissue macrophage infiltration and CCR2 expression. To determine the role of tnf-alpha on adipose tissue macrophage infiltration we bred tnf-alpha deficient mice onto the leptin receptor deficient background and compared obese mice with and without tnf-alpha. Immunohistochemical analysis demonstrated significantly greater percentage of Mac-3 positive cells in the epididymal fat tissue of the obese tnf-alpha wild-type versus the obese tnf-alpha deficient mice (db/db tnf wt: 12.7 + 1.2 %; db/db tnf deficient: 6.5 + 1.0%; p=0.0026; n=3 per group). RT-PCR from adipose tissue revealed a three-fold elevation in CCR2 expression in the obese tnf-alpha wild-type mice compared to the obese tnf-alpha deficient mice. To determine whether CCR2 elevation in the adipose tissue was mediated by adipocyte tnf-alpha or macrophage tnf-alpha, we performed bone marrow transplantation from tnf-alpha deficient and wild-type mice to wild-type recipients. Fifteen weeks following transplantation we examined the expression of adipose derived cytokines via RT-PCR. Importantly, tnf-alpha was found to be reduced greater than 50% (n=5 per group; p=0.007) in the mice receiving tnf-alpha deficient bone marrow demonstrating an important contribution of macrophage tnf-alpha towards adipose tissue tnf-alpha. Furthermore, CCR2 expression was also significantly decreased in mice receiving tnf-alpha deficient marrow (tnf-alpha wt: 4.6 + 0.6; tnf deficient: 2.1 + 0.8; p=0.013; n=5 per group) providing evidence that macrophage derived tnf-alpha can mediate a significant change in CCR2 expression. These findings indicate a critical role for tnf-alpha towards adipose tissue inflammation.
Abstract 4189: Gender Difference in Inflammatory Markers: What is the Contribution of Visceral Adiposity?
Authors: Cartier Amélie , Côté Mélanie , Lemieux Isabelle , Pérusse Louis , Tremblay Angelo , Bouchard Claude , Després Jean-Pierre
Published: April 2024

Several studies have reported a gender difference in inflammatory markers associated with obesity. Indeed, whereas C-reactive protein (CRP) concentrations have been found to be higher in pre-menopausal women compared to men, interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels have been found to be lower in women than in men because of the inhibitory effect of estrogens on the expression of inflammatory genes. Since body fat distribution is very different between men and pre-menopausal women, the contribution of visceral adipose tissue (VAT) to the gender difference in inflammatory markers is a question of clinical relevance. To examine this issue, plasma CRP, IL-6 and TNF-α levels were measured in a sample of 195 healthy men (age: 41.7±14.9 years) and 139 healthy women (age: 36.6±11.2 years). Pre-menopausal women were characterized by lower plasma TNF-α levels (1.57±0.59 pg/mL vs.1.85±0.99 pg/mL, p=0.001) and higher CRP concentrations (1.91±1.77 mg/L vs. 1.65±1.78 mg/L, p=0.04) than men whereas the IL-6 levels did not differ between genders. Significant positive relationships were observed between VAT accumulation and CRP concentrations in men (r=0.43, p<0.0001) and in women (r=0.42, p<0.0001), or IL-6 in men (r=0.42, p<0.0001) and in women (r=0.51, p<0.0001). Regression analyses showed that gender did affect the associations between VAT and CRP. In order to investigate the contribution of visceral adiposity to the gender variation in inflammatory markers, 85 men and 85 pre-menopausal women were individually matched on the basis of similar VAT accumulation. After such matching procedure, women still had significantly higher CRP levels than men (2.07±1.88 and 1.57±1.84 mg/L, p=.01) whereas no differences were observed in IL-6 and TNF-α concentrations. Thus, these results suggest that the gender difference in CRP levels is not entirely explained by the greater amount of VAT generally observed in men.
Abstract 570: Catecholaminergic Polymorphic Ventricular Tachycardia - a Link between Mutation and Arrhythmia
Authors: Iyer Vivek , Hajjar Roger J , Armoundas Antonis A
Published: April 2024

In this study, we investigate the mechanistic underpinnings of catecholaminergic polymorphic ventricular tachycardia (CPVT), a hereditary arrhythmia that leads to exercise- and stress-induced sudden cardiac death in young adults with structurally normal hearts. Recently, several mutations in cardiac calsequestrin (CSQN2) and the cardiac ryanodine receptor (RyR2) have been linked to CPVT. These mutant genes have been shown to affect RyR2 gating, however, the precise mechanisms by which they give rise to triggered activity remain uncertain. We modified a detailed mathematical model of the human left-ventricular subepicardial myocyte, using recently obtained experimental data, to study the aberrant calcium release events observed in mutant myocytes. First, CSQN2 mutations were modeled, by simulating disrupted luminal SR Ca
2+
sensing in the release process (the rate of release termination and rate of recovery from inactivation were increased). Second, a model for mutant RyR2 myocytes was formed by simulating the impaired coupled gating characteristic of reduced FKBP12.6 (calstabin) binding to the RyR2. Both models give rise to delayed afterdepolarizations (DADs) when paced in the presence of simulated isoproterenol. The mechanism for DADs in CSQN2 mutants appears to be secondary to premature recovery of receptors from a luminal calcium-dependent refractory state. In RyR2 mutants, DADs arise from receptors that activate with less synchrony, resulting in hyperactive, “leaky” receptors. Overall, these results provide plausible mechanisms by which defects in RyR2 gating may lead to the cellular triggers of arrhythmia, with implications for the development of targeted therapy.
Abstract 573: Abnormal Impulse Propagation and Susceptibility to Ventricular Tachycardia in a Murine Model of Oculodentodigital Dysplasia
Authors: Kalcheva Nellie , Wang Zhiyong , Sandeep Nefthi , Fishman Glenn I
Published: April 2024

Mutations in the gene encoding connexin43 (Cx43), have been identified in families with oculodentodigital dysplasia (ODDD), a dominantly inherited disorder with pleiotropic phenotypic manifestations. In one family with ODDD due to an isoleucine to threonine missense mutation at residue 130 (I130T), several individuals developed cardiac rhythm disturbances including ventricular tachycardia and sudden cardiac death. To explore the molecular pathology linking Cx43 mutations with arrhythmic behavior, we established a murine model of ODDD by introducing the disease causing I130T mutation into the Cx43 gene through homologous recombination. Approximately 20% of heterozygous Cx43-I130T mutant mice died in the immediate perinatal period, whereas the other 80% have survived for at least 5 months. Heterozygous mutant mice develop hindlimb syndactyly - a common phenotypic characteristic of humans with ODDD. The hearts of mutant mice did not display gross anatomical abnormalities and evaluation of left ventricular chamber size, wall thickness and contractile performance as assessed by echocardiography was not significantly different than wildtype littermates. Western blot analysis of heterozygous I130T mice demonstrated substantially less than 50% of wildtype levels of Cx43, whereas Cx43 transcript levels were normal, suggesting a dominant-negative effect of the mutation on Cx43 protein stability. Immunohistochemical stainining demonstrated less efficient trafficking of Cx43 to the intercaled disk in mutant hearts. Optical mapping studies of impulse propagation in Langendorff-perfused hearts demonstrated significant slowing (p<0.05) of conduction velocity in both the longitudinal (.61 ± .03 m/s vs .74 ± .04 m/s) and transverse (.30 ± .02 m/s vs .43 ± .02) directions in mutant hearts compared to wildtype littermates. Moreover 7/7 mutant hearts developed spontaneous and inducible sustained monomorphic ventricular tachycardia where 0/7 wildtype littermates developed sustained arrhythmias. In summary, Cx43-I130T mutant mice display phenotypic features of human ODDD including syndactyly and rhythm disturbances. Additional study of this novel mouse model will provide insights into aberrant function of Cx43 and pro-arrhythmic behavior.
Abstract 580: Skeletal Myoblasts and Bone Marrow-Derived Cells Enhance the Contractile Function of Isolated Failing Cardiomyocytes in Co-culture
Authors: Lee Joon , Stagg Mark A , Soppa Gopal K , Siedlecka Urszula , Yacoub Magdi H , Terracciano Cesare M
Published: April 2024

Cell transplantation has been shown to enhance ventricular function in heart failure. However, the low numbers of surviving transplanted cells can not explain the functional myocardial improvement directly, and the cellular mechanisms responsible remain unknown. We hypothesized that transplanted cells influence the native myocardium by paracrine mechanisms, and investigated the
in vitro
effects of bone marrow mononuclear cells or skeletal myoblasts on neighboring cardiomyocytes isolated from a rat model of heart failure. Myocardial infarction was induced in adult female Sprague-Dawley rats by left coronary artery ligation. Left ventricular ejection fraction after 3 weeks was 35.5 ± 2.0%. Isolated left ventricular myocytes were cultured (density 5.2 cells/mm
2
) on their own (Control) or with either bone marrow mononuclear cells (BM, density 52 cells/mm
2
) or skeletal myoblasts (SK, density 5.2 cells/mm
2
). After 48 hours of culture with SK or BM cardiomyocyte relaxation speed was increased (time to 50% relaxation, in ms - Control 34 ± 6 [
28
]; BM 18 ± 3 [
16
]
p <
0.05 vs Control; SK 13 ± 2 [
20
]
p <
0.05 vs Control). The decay time course of the Ca
2+
transient, assessed by indo-1 fluorescence, was also hastened by SK (time to 50% decay, in ms – HF 22 ± 2 [
29
]; BM 18 ± 2 [
17
]
ns
; SK 13 ± 1 [
17
]
p <
0.05 vs Control). SK also increased the contraction amplitude compared to Control (sarcomere shortening, in μm - HF 0.046 ± 0.006 [
28
]; BM 0.055 ± 0.01 [
16
]
ns
; SK 0.091 ± 0.014 [
20
]
p <
0.05 vs Control). We conclude that bone marrow mononuclear cells and skeletal myoblasts enhance cardiomyocyte function in co-culture, demonstrating that paracrine mechanisms are involved. This may account for the functional improvement seen after cell transplantation.
Abstract 581: Rapid Down-Regulation of Connexin43 after Stretch-Induced Early Myocardial Hypertrophy
Authors: Bupha-Intr Tepmanas , Varian Kenneth D , Janssen Paul M
Published: April 2024

Gap junctions are important for cardiac conduction and consequent synchronized contraction. Heterogeneous gap junction distribution or reduced numbers of gap junctions can cause arrythmogenic components in hypertrophic cardiomyopathy. It is known that during end stage failure expression of critical gap junction proteins are down-regulated. It is unknown if in early stages of hypertrophy, mechanical load plays a role in reduction of gap junction protein levels. To assess the hypothesis that regulation of connexin43 expression occurs during early stage of hypertrophic induction, expression was measured in cultured multicellular myocardium subjected to high mechanical loading. Right ventricular trabeculae from rabbit hearts were subjected to high mechanical load or no load (slack) conditions in a multicellular muscle culture system. These small ventricular trabeculae were continuously electrically stimulated at 1 Hz at 37 Celsius, and isometric contractions were recorded for periods 24 – 48 hours. Muscles exposed to high load gradually increased developed force with time. Average developed force measured at 24 h was 178 +/− 22 % (n=12, P<0.05) from starting values. We observed a significant increase in muscle diameter, by 4.3 +/− 1.4 (n=8, P<0.05) and 17.4 +/− 3.7 % (n=14, P<0.05) after 24 and 48 hours of high load contractions. Edema was absent, indicating myocyte hypertrophy. Protein quantification showed a down-regulation of connexin43 in stretched muscles to 49 +/− 14% (n=5, P<0.05) and 31 +/− 10% (n=5, P<0.05) of control fresh muscles after 24 and 48 h of high load, respectively. There was no significant different in connexin43 expression between fresh control myocardium and muscles cultured and stimulated in absence of load for 48 hours. Reduced connexin43 levels resulted in a functional impairment of gap junctions. Only in non-stretched muscles iontophoretically loaded bis-fura 2 into a single central myocyte could spread form cell to cell with a good success rate (~80 –90%). Out of 8 high load muscles we were able to spread dye via gap junctions in only a single muscle, and this only at levels well below normal. We conclude that mechanical loading alone can decrease expression and function of gap junctions during early cardiac hypertrophy.
Abstract 591: Non-Invasive Analysis of Oxidative Stress in Myocardial Remodeling and Failure in Mice Using in vivo Electron Spin Resonance (ESR) Spectroscopy
Authors: Ide Tomomi , Yamato Mayumi , Yoshida Masayoshi , Utsumi Hideo , Masaki Ikeuchi , Tsutsumi Takaki , Inoue Takahiro , Shiba Takeshi , Tsutsui Hiroyuki , Sunagawa Kenji
Published: April 2024

Oxidative stress plays an important role in the development and progress of myocardial remodeling and failure. We have demonstrated that the generation of reactive oxygen species (ROS) is enhanced in the tissue homogenates obtained from the failing hearts in vitro by electron spin resonance (ESR) spectroscopy (Ide, Circ Res 2000, 86, 152). However, there is no direct evidence of ROS generation in the hearts in vivo. Therefore, the aim of this study was to assess the time-dependent changes of ROS generation in the hearts after myocardial infarction(MI) using a technique of in vivo ESR measurement that has been developed for direct and non-invasive analysis of ROS generation in living animals.We created MI in mice by ligating the left coronary artery and performed in vivo ESR analysis at day 2, 7, 14, and 28 after MI. The in vivo generation of ROS was analyzed by the ESR signal decay of methoxy-PROXYL, a tissue permeable spin probe, injected intravenously. Left ventricular (LV) function was assessed by echocardiography. The ESR signal decay measured at the chest of mice was not changed in MI at day 2, but was increased in MI compared to sham-operated mice at day 7 (Sham vs MI; 0.122±0.005 vs 0.142±0.007/min; p<0.05)and further increased at day 14(0.123±0.004 vs 0.162±0.009/min, p<0.01) and 28 (0.119±0.004 vs 0.161±0.010/min, p<0.01). The accelerated ESR signal decay was associated with the progression of LV dilatation and dysfunction. The increased ESR signal decay in MI was completely suppressed by the administration of antioxidant, Tiron. The ESR signal decay was comparable between groups when measured at the head or the abdomen, indicating that the increase of the signal decay was due to the ROS generation within the heart. It was further confirmed by the increased ESR signal decay in the cardiac homogenates obtained from MI mice. The present study provided the direct evidence in the post-MI living mice that ROS were generated within the hearts during the progression of remodeling and failure.
Abstract 608: Valsartan Reverses Post-Translational Modifications of ATP Synthase D-Chain During Prolonged Post-Ischemic Reperfusion
Authors: Jugdutt Bodh I , Sawicki Grzegorz
Published: April 2024

We hypothesized that reperfused myocardial infarction (RMI) induces post-translational modifications (PTMs) of the metabolic enzyme mitochondrial ATP synthase D-chain (ATP/D) which are reversed by the angiotensin II type 1 receptor (AT
1
R) blocker valsartan. We applied a pharmaco-proteomics approach to detect regional differences in PTMs of ATP/D in ischemic (IZ) and non-ischemic (NIZ) zones of hearts subjected to
in vivo
RMI (90 min left anterior descending coronary occlusion; 120 min reperfusion) in dogs randomized to placebo or valsartan. We measured hemodynamics and left ventricular (LV) function (2D-Echocardiogram/ Doppler) and identified/analyzed ATP/D using 2D electrophoresis, PD Quest, and in-gel trypsin digestion of protein spots (Fig. A

) followed by mass spectrometry, and FindMod tool for finding potential PTMs. Compared to sham, RMI induced ischemic injury and systolic and diastolic dysfunction in the placebo group and these were attenuated by valsartan. Compared to the NIZ, RMI increased ATP/D in the IZ (nearly 2-fold) and this was normalized by valsartan (Fig. B

). Importantly, RMI increased hydroxylation of ATP/D, S-nitrosylation of cysteine-100, nitration of tyrosine-80 and -225, and hydroxylation of lysine-182 followed by its myristoylation (Fig. C

). Valsartan reduced ATP/D hydroxylation, abolished the PTMs including lysine myristoylation in the IZ, and additionally triggered phosphorylation of serine-76 in both the IZ and NIZ. Valsartan-induced cardioprotection is associated with reversal of PTMs of ATP/D during RMI. This new pleiotropic effect of AT
1
R blockade suggests that PTMs may represent a novel therapeutic target after RMI.
Abstract 610: The Pig Heart Harbors Cardiac Stem-Progenitor Cells which Respond to Increasing Growth Factor Stimulation Regenerating the Infarcted Myocardium
Authors: Ellison Georgina M , Torella Daniele , Karakikes Ioannis , Nieto Alejandro Diego , Fernandez Fellipe , Perez-Martinez Claudia , Perez Armando , Nadal-Ginard Bernardo
Published: April 2024

Recent reports on murine models have raised the possibility of regenerating contractile myocardial tissue by
in situ
activation and mobilization of cardiac stem/progenitor cell (CSC) by growth factors (GF). Extrapolation of murine results to the human are doubtful because the human requires ~ 5x10
3
larger regenerated mass. We sought to establish the effects of CSC
in situ
mobilization by intracoronary injections of IGF-1 and HGF after MI in pigs. To this aim, in 23 female Yorkshire pigs, a 75 min PTCA LAD occlusion was used to induce acute MI. Five hours later, IGF-1 and HGF were administered to 16 instrumented pigs. Total doses of GF ranged from 200 to 800ng/ml. Saline was injected in the other 7 pigs with MI. Three pigs received a second dose of GFs at 14 days. All pigs were sacrificed at 28 days after MI and GF administration. To track myocardial regeneration, BrdU was administered via osmotic pumps. Cardiac function was measured by echocardiography and LV catheterization. Cardiac tissue from sham operated pigs was collected and CSCs extracted for
in vitro
analyses. These CSCs displayed stem cell properties of clonogenicity, self-renewal and multipotency similar to rodent CSCs. Moreover, they expressed functional IGF-1R and c-met receptors. The GF-treated infarcted heart showed a significant increase in the number of c-kit
pos
CSCs in the border of the infarct and even higher in the ischemic area. Most of these CSCs were BrdU
pos
/Ki-67
pos
. Many c-kit
pos
cells expressed the transcription factors, MEF-2C, Ets-1 and GATA6 indicative of myocyte, endothelial cell and smooth muscle differentiation, respectively. Interestingly, the infarcted area was substantially replaced by new myocardium in direct correlation to the amount of GF administered. These hearts had a significant and increasing number of small BrdU
pos
(up to 14±3%) and Ki-67
pos
(up to 12±2%) myocytes. Moreover, newly formed vascular structures were evident in the infarcted myocardium. Myocardial regeneration was absent in untreated pigs. Importantly, LV function was significantly improved in GF treated, compared to controls. Therefore, it is possible and practical to produce effective myocardial regeneration post-MI in hearts the size of the human’s following intracoronary injection of GFs.
2006 Charles T. Dotter Memorial Lecture—Cardiac Surgery: Pre- & Post-Operative Insights From MR & CT
Authors: White Richard
Published: April 2024

Advancements in MR and CT imaging of the cardiovascular system have permitted unique insights into the appearance and behavior of the cardiac chambers, myocardium, coronary arteries, pericardium, and proximal great vessels in disease states directly involving or indirectly affecting (eg, such as due to valve disease) these structures. However, the impact of the 3D anatomic, functional, tissue-characterizing, or flow-quantification capabilities of these two noninvasive tomographic imaging modalities specifically on pre–cardiac surgery planning and/or post–cardiac surgery monitoring has not often been addressed. With concurrent advances in catheter-based therapy, there has been significant reduction in the volume of traditional cardiac surgical procedures such as coronary artery bypass grafting. Because of the life-saving nature of these surgical alternatives, traditional surgeries, and medical therapies, older patients with complicated medical histories, including prior interventions, leading to highly patient-specific cardiac conditions, are more and more commonly cardiac surgery candidates. Thus, there is increasing need for highly specialized and individualized imaging in order for cardiac surgeons to understand the specific details of such patients’ current cardiac anatomic and physiological abnormalities in the context of their past disease course and history of therapy to plan future surgical treatments. Cardiac surgical procedures performed at major heart centers that benefit from insights provided by cardiac MR and CT include ventricular restoration of the dilated dysfunctional left ventricle, myocardial revascularization of the chronically ischemic left ventricle, septal myectomy for hypertrophic obstructive cardiomyopathy, pericardiectomy for constrictive or adhesive pericardial disease, cardiac mass resection, and aortic root and/or valve replacement.
2006 Stroke Council Award and Lecture—Patent Foramen Ovale and Stroke: What We Have Learned and What We Still Need to Know
Authors: Saver Jeffrey
Published: April 2024

Management of patients with cryptogenic stroke and a patent foramen ovale (PFO) is a common clinical dilemma for cardiologists, neurologists, and primary care physicians and is a rapidly growing public health challenge for society. Between 50 000 and 100 000 Americans each year present with a PFO and an ischemic stroke of otherwise undetermined etiology. Collaborative studies by cardiovascular and cerebrovascular physician-scientists over the past 2 decades have advanced our understanding of the epidemiology, pathophysiology, and management of patients with patent foramen ovale and ischemic brain disease. The recurrent stroke rate among young cryptogenic stroke patients with a PFO is modest but higher than normal for age. Coexisting atrial septal aneurysm is a substantial—and the only definite—potentiator of stroke risk in patients with PFO, but PFO size, degree of functional shunting, and coexisting hyper-coagulable state likely are additional risk factors. Pelvic computed tomographic and magnetic resonance venography has improved our ability to detect source venous thromboemboli and underlies new management strategies. Close analysis of randomized clinical trial results suggests that brain imaging demonstration of a superficial convexity stroke location indicative of a highly probable embolic stroke top may usefully guide the selection of anticoagulation versus antiplatelet therapy in medically managed patients. The completion of ongoing randomized clinical trials comparing percutaneous closure devices with medical management is likely to be hastened by the recent withdrawal of humanitarian device exemption approvals and is urgently needed to provide definitive data to guide management of these patients with a linked disorder of heart and brain.
2009 George E. Brown Memorial Lecture—Marfan Syndrome and Related Disorders: From Molecules to Medicines
Authors: Dietz Harold C.
Published: April 2024

Our lab studies molecular determinants of vessel wall homeostasis, with particular emphasis on molecules and pathways that contribute to aortic aneurysm. The study of Marfan syndrome (MFS), an autosomal dominant condition with a strong predisposition for aortic root aneurysm and dissection, has provided a tractable means to gain a foothold in the pathogenesis of this complex phenotype. Our initial studies demonstrated that MFS is caused by mutations in the extracellular matrix protein fibrillin-1. Early pathogenetic models that singularly invoked inherent weakness of the tissues as the driving force in disease progression boded poorly for the development of productive treatment strategies and failed to reconcile multiple disease manifestations, including bone overgrowth, myxomatous valve changes, and muscle and fat hypoplasia. Using mouse models of MFS, we demonstrated that fibrillin-1 is not simply a structural protein but rather regulates the local bioavailability and activation of the growth factor transforming growth factor (TGF)
β
. Many important manifestations of MFS, including emphysema, valve degeneration, myopathy, and aortic aneurysm, could be attenuated or prevented in fibrillin-1–deficient mice upon systemic administration of TGF
β
antagonists. Similar protection was achieved through the use of the angiotensin II type 1 receptor blocker (ARB) losartan, which lowers both blood pressure and TGF
β
signaling and is in widespread clinical use for the treatment of hypertension. These observations led to the first clinical trial for MFS that is based upon a refined mechanistic understanding of disease. We now have performed comprehensive interrogation of a modifier network in mouse models of MFS. These data reveal parsing of the angiotensin II signaling cascades in the pathogenesis and prevention of aortic aneurysm. Signaling through the type 2 (AT2) receptor is protective, whereas loss of AT2 signaling accelerates disease and attenuates the protection afforded by ARBs, suggesting that losartan provides protection, at least in part, through shunting of angiotensin II signaling through AT2. We also demonstrate a predominant role of noncanonical TGF
β
signaling in the pathogenesis of ascending aortic aneurysm and show that the mechanism of AT2-mediated protection derives from cross-talk with this pathway. Taken together, these data explain why ARBs markedly outperform angiotensin-converting enzyme inhibitors in our mouse model of MFS. They also define noncanonical TGF
β
and AT2 signaling as prognostic and therapeutic modifiers of vascular disease and provide rationale and incentive for additional clinical trials in MFS and related disorders.
Antiarrhythmic Drug Therapy for Sustained Ventricular Arrhythmias Complicating Acute Myocardial Infarction
Authors: Piccini Jonathan P.
Published: April 2024

Abstract #2363

Jonathan P. Piccini, Phillip J. Schulte, Karen S. Pieper, Rajendra H. Mehta, Duke Clinical Res Inst, Durham, NC; Eric J. Topol, Scripps Translational Science Inst, La Jolla, CA; Harvey D. White, Auckland City Hosp, Auckland, New Zealand; Frans Van de Werf, Univ Hosp Leuven, Leuven, Belgium; Diego Ardissino, Univ of Parma, Parma, Italy; Robert M. Califf, Christopher B. Granger, E. Magnus Ohman, John H. Alexander, Duke Clinical Res Inst, Durham, NC

Jonathan P. Piccini, 2009 Finalist and Presenting Author
BRCA1 Is a Novel Regulator of Endothelial Function and Limits Atherosclerosis
Authors: Singh Krishna K
Published: April 2024

Abstract #4219

Krishna K Singh, Praphulla C Shukla, Adrian Quan, St Michaels Hosp, Toronto, ON, Canada; Mohammed Al-Omran, King Saud Univ, Riyadh, Saudi Arabia; Paul Jurasz, Univ of Alberta, Edmonton, AB, Canada; Fina Lovren, Yi Pan, Christine Brezden-Masley, St Michaels Hosp, Toronto, ON, Canada; Alistair J Ingram, McMaster Univ, Hamilton, ON, Canada; Lee Errett, Hwee Teoh, Subodh Verma, St Michaels Hosp, Toronto, ON, Canada

Krishna K Singh, 2009 Finalist and Presenting Author
Nurse-led Titration of Beta-blockers Can Improve Outcomes in Chronic Heart Failure Patients in the Community
Authors: Driscoll Andrea
Published: April 2024

Abstract #905

Andrea Driscoll, Henry Krum, Andrew Tonkin, Monash Univ, Melbourne, Australia; BENCH study group

Andrea Driscoll, 2009 Finalist and Presenting Author
Association of ST2 Levels With Cardiac Structure and Function and Mortality in Outpatients
Authors: Daniels Lori B.
Published: April 2024

Abstract #2370

Lori B. Daniels, Univ of California, San Diego, La Jolla, CA; Paul Clopton, VA San Diego Healthcare System and Univ of California, San Diego, San Diego, CA; Kimberly Tran, VA San Diego Healthcare System, San Diego, CA; Alan S. Maisel, VA San Diego Healthcare System and Univ of California, San Diego, San Diego, CA

Lori B. Daniels, 2009 Finalist and Presenting Author
DNA Sequence Variants Related to Plasma Triglycerides or High-Density Lipoprotein Cholesterol and Risk of Myocardial Infarction
Authors: Kathiresan Sekar
Published: April 2024

Abstract #1807

Sekar Kathiresan, Benjamin F. Voight, Massachusetts General Hosp, Boston, MA; Myocardial Infarction Genetics Consortium

Sekar Kathiresan, 2009 Finalist and Presenting Author
Abstract 4842: Is Altered Collagen Turnover Related to the Development of Stiff Arteries and Hearts in Chronic Kidney Disease?
Authors: Edwards Nicola C , Kirkwood Helen , Cramb Robert , Steeds Richard P , Ferro Charles J , Townend John N
Published: April 2024

Introduction Cardiovascular mortality is increased in chronic kidney disease (CKD) in a graded inverse relationship with glomerular filtration rate (GFR). We and others have demonstrated increased arterial stiffness which also has a graded relationship with GFR and is of prognostic significance. Experimental studies have shown increased collagen associated proteins in the intimal and medial arterial layers which appear to precede vascular calcification in CKD. We hypothesised that active, collagen dependent, fibrotic processes might increase arterial stiffness and compromise ventricular relaxation thereby contributing to the high levels of cardiovascular disease.

Methods We studied 117 patients with early stage CKD (mean eGFR 51 ml/min/1.73m
2,
range 30 – 89), controlled hypertension (<130/85mmHg) no history of cardiovascular disease or diabetes. Arterial stiffness was assessed using pulse wave velocity (PWV) by applanation tonometry and aortic distensibility in the ascending aorta by CMR (1.5T). Early myocardial relaxation velocities (Em) and E/Em ratio (marker of LVEDP) were measured by echocardiography. Serological collagen turnover markers; amino-terminal propeptide of procollagen type III (PNIIIP a measure of collagen synthesis) and C-terminal telopeptide of type I collagen (CTx a measure of collagen degradation), were measured by radioimmunoassay and ECLIA immunoassay.

Results PNIIIP was inversely correlated with eGFR (
r
= 0.52 p<0.01), aortic distensibilty (
r
= 0.23 p<0.05) and Em (
r
= 0.24 p<0.05) and positively correlated with PWV (
r
= 0.23 p<0.05), and E/Em (
r
= 0.2 p<0.05). CTx was inversely correlated with eGFR (
r
= 0.31 p<0.01) but was not correlated with markers of arterial or ventricular stiffness

Conclusion Collagen synthesis, arterial and ventricular stiffness are all increased with deteriorating renal function even from the earliest stages of CKD. This suggests that collagen metabolism plays an important role in the development of arterial and myocardial stiffness in CKD. Collagen turnover is a possible new therapeutic target in the prevention of cardiovascular disease in CKD.
Abstract 4855: Long-term Effect of Efonidipine Therapy on Plasma Aldosterone and Left Ventricular Mass Index in Patients With Essential Hypertension
Authors: Tsutamoto Takayoshi , Nishiyama Keizo , Yamaji Masayuki , Kawahara Chiho , Fujii Masanori , Yamamoto Takashi , Horie Minoru
Published: April 2024

Background. Aldosterone (ALD) breakthrough often occurs and is an important issue during long-term treatment with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB). Previous studies showed that ALD breakthrough the incidence of ALD breakthrough was between 22–53% after 12 months. Recently, it has been reported that efonidipine, a T-type and L-type calcium channel blocker, decreases plasma levels of ALD. However, long-term effects of efonidipine on plasma levels of ALD and left ventricular mass index (LVMI) remain unknown in patients with hypertension.

Methods and Results. Sixty stable outpatients with essential hypertension who had received amlodipine and ACE-I or ARB for more than one year were randomized to two groups [amlodipine group (n=30): continuous amlodipine treatment at a stable dose; efonidipine group (n=30): amlodipine (5mg/day) was changed to efonidipine at a dose of 40mg/day]. There was no difference in the baseline characteristics including LVMI and plasma levels of ALD between two groups. In the amlodipine group, there were no significant changes in blood pressure, LVMI or plasma levels of ALD during 18 months. In the efonidipine group, blood pressure did not change after replacement of amlodipine by efonidipine, although there was a significant decrease in plasma levels of ALD after 6 months and the decrease of ALD was sustained for 18 months (106±49 pg/mL at baseline, 76±30 pg/mL at 6 months, 79±43 pg/mL at 9 months, 77±34 pg/mL at 18 months) and plasma ALD level eventually increased again in only 2 patients (7% aldosterone breakthrough). In addition, LVMI was significantly decreased after 18 months (121±25 vs. 114±21 g/m2, p<0.05). There was a significant correlation between changes in LVMI and % changes of ALD in the efonidipine group (r=0.427, p=0.018).

Conclusion. These findings indicate that the effect of efonidipine on suppression of plasma ALD was sustained for at least 18 months and that long-term efonidipine therapy decreases LVMI in patients with essential hypertension
Abstract 4863: Emergency Cardiac Catheterization for “False-Positive” ST-Segment Elevation Myocardial Infarction
Authors: Nfor Tonga , Hashim Hani , Kostopoulos Louie , Gupta Anjan , Bajwa Tanvir , Allaqaband Suhail
Published: April 2024

Introduction
: In a push to treat STEMI patients with primary PCI within 90 minutes of door-to-balloon time, medical institutions have developed emergency cardiac catheterization laboratory activation protocols that bypass other routine clinical assessments. This has raised concerns about more frequent catheterizations in patients who may not need them. Our study objective was to determine the incidence, predictors and prognosis of false-positive STEMI.

Methods
: We studied a prospective cohort of patients diagnosed with STEMI who received emergency cardiac catheterization with intention of primary PCI between January 2005 and December 2007 at a tertiary care center serving more than 20 community hospitals. False-positive STEMI was defined as absence of a clear culprit lesion on coronary angiography. Multivariate logistic regression was used to identify independent predictors of false-positive STEMI.

Results
: Of 489 patients who received emergency cardiac catheterization indicated for STEMI, 54 (11.0%, 95% CI 8.3%–13.8%) had no culprit lesion on coronary angiography. Independent predictors of false-positive STEMI identified on multivariate analysis are shown in the table

. Among patients with false-positive STEMI, 22.2% had a serious cardiac diagnosis by catheterization. One-year incidence of acute myocardial infarction or PCI was 7.5% in patients with a culprit lesion vs. 1.9% in patients with no culprit lesion (p=0.08). One-year mortality was 6.5% among patients with a culprit lesion vs. 3.7% without (p=0.22).

Conclusion
: False-positive STEMI is common among patients undergoing emergency cardiac catheterization. A better understanding of the identifiers for false-positive STEMI may help physicians quickly reassess the utility of emergency cardiac catheterization when the diagnosis of STEMI is in doubt.

Independent Predictors of False-Positive ST-Segment Elevation Myocardial Infarction From Multivariate Analysis
Abstract 4866: Red Blood Cell and Mixed Types of Aspirated Intracoronary Thrombi Obtained From Patients With Acute Myocardial Infarction Predict Long-Term Mortality
Authors: Yunoki Kei , Naruko Takahiko , Komatsu Ryushi , Shirai Nobuyuki , Nakagawa Masashi , Sugioka Kenichi , Ikura Yoshihiro , Kusano Kengo F , Itoh Akira , Haze Kazuo , Ueda Makiko
Published: April 2024

Background:
Oxidative stress and inflammatory processes are of major importance in plaque instability. We demonstrated previously that elevated plasma oxidized low-density lipoprotein (ox-LDL) levels are related to plaque instability. In this study, we investigated whether plasma ox-LDL levels were related to the types of intracoronary thrombi (ICT) obtained by percutaneous thrombectomy in 130 patients within 12 hours of onset of acute myocardial infarction (AMI). We also analyzed whether individual types of ICT were related to long-term mortality.

Methods:
Frozen samples of aspirated ICT from 130 AMI patients were studied. Serial sections were investigated immunohistochemically using antibodies against platelets, red blood cells (RBCs) (glycophorin A) and neutrophils (CD66b and MPO). The ICT were classified into three types: platelet (PL) type (>70% of the ICT surface area consisting of platelets; n=45), RBC type (>70% of the ICT surface area consisting of RBCs; n=31) or mixed type (mixture of platelets and RBCs; n=54). We also measured plasma ox-LDL levels on admission using a specific monoclonal antibody.

Results:
Plasma ox-LDL levels were significantly higher in the RBC type than in the PL type (RBC, 1.89±1.84; mixed, 1.35±1.21; PL, 1.01±0.94 ng/5
μ
g LDL protein; RBC versus PL, P<0.05). Quantitative analysis demonstrated the percentage of MPO-positive neutrophils in the RBC or mixed types were significantly higher than in the PL type (RBC, 35±16%; mixed, 36±18%; PL, 23±17%; RBC versus PL, P<0.05 and mixed versus PL, P<0.005). Over a mean follow-up period of 33.5 months (range 1 day – 87.6 months), there were 17 cases (13%) of cardiac death. Kaplan-Meier survival curves showed that RBC and mixed types had significantly worse mortality than the PL type (P=0.040 by log-rank test). Multivariate analysis demonstrated that RBC and mixed types were independent determinants of long-term mortality (OR, 5.34; 95%CI, 1.083 – 26.37, P=0.039).

Conclusions:
The present study demonstrates that neutrophil activation and MPO release in mixed or RBC types of thrombi may play a role in generating excessive pro-oxidants. In addition, the presence of thrombi with RBC and mixed types is an independent predictor of long-term mortality.
Abstract 4870: Mechanisms Leading to Impaired Endothelial-vasoprotective Properties of High Density Lipoprotein (HDL) in Patients With Coronary Disease (CAD)
Authors: Besler Christian , Heinrich Kathrin , Rohrer Lucia , Yonekawa Keiko , Doerries Carola , Manes Costantina , Müller Maja , Templin Christian , Corti Roberto , Maier Willibald , Wyss Christophe , Alibegovic Jasmina , Kucher Nils , von Eckardstein Arnold , Luscher Thomas F , Landmesser Ulf
Published: April 2024

Background:
HDL-raising therapies are currently intensely evaluated as a potential novel therapeutic strategy in patients with CAD. However, vascular effects of HDL have been observed to be highly variable. The aim of the present study was therefore to characterize mechanisms leading to altered endothelial-vasoprotective properties of HDL in patients with CAD.

Methods:
HDL was isolated from patients with stable CAD (sCAD), an acute coronary syndrome (ACS) and healthy subjects (HS; n=20 –25) by sequential ultracentrifugation. The effects of HDL on endothelial nitric oxide (NO) production, endothelium-dependent, NO-mediated vasodilation, signaling pathways leading to eNOS activation and endothelial superoxide production (ESR spectroscopy analysis) were examined. HDL-associated paraoxonase (PON) activity/content and endothelial binding of HDL (radioactive 125I-labelling of HDL) were characterized. Moreover, the role of eNOS and PON for anti-inflammatory properties of HDL were determined.

Results:
HDL from HS, but not HDL from sCAD/ACS patients, potently stimulated endothelial NO production. HDL from HS increased endothelial Akt, eNOS-Ser1177-phosphorylation and eNOS-Thr495-dephosphorylation, that was not observed with HDL from sCAD/ACS patients. Endothelial binding capacity of HDL was markedly reduced in patients with CAD. PON activity was reduced (−62.2% and −70.4% vs. HS, P<0.001), whereas PON1 content was increased in HDL from sCAD/ACS patients as compared to HDL from HS, suggesting inactivation of HDL-associated PON in CAD. Inhibition of PON activity prevented the capacity of HDL from HS to stimulate Akt/eNOS phosphorylation, endothelial NO production, NO-dependent vasodilation and to exert anti-inflammatory effects. eNOS siRNA knockdown prevented anti-inflammatory effects of HDL from HS.

Conclusion:
The present study demonstrates that reduced endothelial binding of HDL and inactivation of HDL-associated paraoxonase are major mechanisms leading to impaired endothelial-vasoprotective and anti-inflammatory effects of HDL in CAD patients. HDL-targeted treatment approaches should therefore not only increase HDL levels, but likely more important, restore endothelial-vasoprotective properties of HDL.
Abstract 4879: Overexpression of GTP-Cyclohydrolase I in Vascular Endothelium Prevents Oxidative Stress-Induced eNOS Translocation From Caveolae to Cytosol
Authors: Peterson Timothy E , Katusic Zvonimir S , d’Uscio Livius V
Published: April 2024

GTP-Cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin biosynthesis, an essential co-factor required for enzymatic activity of endothelial nitric oxide synthase (eNOS). Recent studies have suggested that endothelium-targeted overexpression of GTPCH I has vasoprotective effects. Therefore, we hypothesized that in endothelium GTPCH I localization in caveolae protects eNOS against oxidative stress. Human umbilical vein endothelial cells (HUVECs) were incubated with recombinant adenovirus encoding the human GTPCH I gene (Ad-GTPCH I, 100 MOI) or control recombinant adenoviral vector (Ad-ΔE1) for 12 hours in serum-free media. Cells were then fed with growth medium for 48 hours prior to analysis. Using sucrose gradient ultracentrifugation we detected both protein expression and enzymatic activity of GTPCH I in caveolar microdomains of HUVECs. Treatment of Ad-ΔE1 transduced endothelial cells for 24 hours with LY83583 (1
μ
M), a superoxide anion generator, significantly decreased enzymatic activity of GTPCH I in caveolae-enriched membranes (0.49±0.12 pmol neopterin/mg protein; P<0.05 vs. control: 0.92±0.07 pmol neopterin/mg). Furthermore, LY83583 translocated eNOS from caveolae to cytosol in Ad-ΔE1 treated endothelial cells (P<0.05; n=3). This effect was specific because there was no change in caveolin-1 expression and no decrease in cell viability. Treatment of HUVECs with Ad-GTPCH I significantly increased GTPCH I activity in caveolae-enriched membranes (1.37±0.22 pmol neopterin/mg; P<0.05; n=4). Interestingly, LY83583-induced dislocation of eNOS from caveolar membrane fraction was significantly prevented by overexpression of GTPCH I (P<0.05; n=3). Our results suggest that overexpression of GTPCH I increases its enzymatic activity in caveolae. This effect preserves strategically key localization of eNOS in cell membrane during oxidative stress.

This research has received full or partial funding support from the American Heart Association, National Center.