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1.  Clinical Research Priorities in Adult Congenital Heart Disease 
International journal of cardiology  2013;171(3):351-360.
Background
Adult congenital heart disease (ACHD) clinicians are hampered by the paucity of data to inform clinical decision-making. The objective of this study was to identify priorities for clinical research in ACHD.
Methods
A list of 45 research questions was developed by the Alliance for Adult Research in Congenital Cardiology (AARCC), compiled into a survey, and administered to ACHD providers. Patient input was sought via the Adult Congenital Heart Association at community meetings and online forums. The 25 top questions were sent to ACHD providers worldwide via an online survey. Each question was ranked based on perceived priority and weighted based on time spent in ACHD care. The top 10 topics identified are presented and discussed.
Results
The final online survey yielded 139 responses. Top priority questions related to tetralogy of Fallot (timing of pulmonary valve replacement and criteria for primary prevention ICDs), patients with systemic right ventricles (determining the optimal echocardiographic techniques for measuring right ventricular function, and indications for tricuspid valve replacement and primary prevention ICDs), and single ventricle/Fontan patients (role of pulmonary vasodilators, optimal anticoagulation, medical therapy for preservation of ventricular function, treatment for protein losing enteropathy). In addition, establishing criteria to refer ACHD patients for cardiac transplantation was deemed a priority.
Conclusions
The ACHD field is in need of prospective research to address fundamental clinical questions. It is hoped that this methodical consultation process will inform researchers and funding organizations about clinical research topics deemed to be of high priority.
doi:10.1016/j.ijcard.2013.12.034
PMCID: PMC3940155  PMID: 24411207
Congenital Heart Disease; Tetralogy of Fallot; Transposition of the Great Arteries; Fontan Procedure; Survey
2.  ABCC9 is a Novel Brugada and Early Repolarization Syndrome Susceptibility Gene 
International journal of cardiology  2014;171(3):431-442.
Background
Genetic defects in KCNJ8, encoding the Kir6.1 subunit of the ATP-sensitive K+ channel (IK-ATP), have previously been associated with early repolarization (ERS) and Brugada (BrS) syndromes. Here we test the hypothesis genetic variants in ABCC9, encoding the ATP-binding cassette transporter of IK-ATP (SUR2A), are also associated with both BrS and ERS.
Methods and Results
Direct sequencing of all ERS/BrS susceptibility genes was performed on 150 probands and family members. Whole-cell and inside-out patch-clamp methods were used to characterize mutant channels expressed in TSA201-cells. Eight ABCC9 mutations were uncovered in 11 male BrS probands. Four probands, diagnosed with ERS, carried a highly-conserved mutation, V734I-ABCC9. Functional expression of the V734I variant yielded a Mg-ATP IC50 that was 5-fold that of wild-type (WT). An 18-y/o male with global ERS, inherited an SCN5A-E1784K mutation from his mother, who displayed long QT intervals, and S1402C-ABCC9 mutation from his father, who displayed an ER pattern. ABCC9-S1402C likewise caused a gain of function of IK-ATP with a shift of ATP IC50 from 8.5±2 mM to 13.4±5 μM (p<0.05). The SCN5A mutation reduced peak INa to 39% of WT (p<0.01), shifted steady-state inactivation by −18.0mV (p<0.01) and increased late INa from 0.14% to 2.01% of peak INa (p<0.01).
Conclusion
Our study is the first to identify ABCC9 as a susceptibility gene for ERS and BrS. Our findings also suggest that a gain-of-function in IK-ATP when coupled with a loss-of-function in SCN5A may underlie type 3 ERS, which is associated with a severe arrhythmic phenotype.
doi:10.1016/j.ijcard.2013.12.084
PMCID: PMC3947869  PMID: 24439875
Mutation; ATP-Sensitive Potassium Channel; Sodium Channel; Sudden Cardiac Death; J Wave Syndromes
3.  [No title available] 
PMCID: PMC3947905  PMID: 24365609
4.  Cancer therapy-induced autonomic dysfunction in early breast cancer: Implications for aerobic exercise training 
International journal of cardiology  2013;171(2):e50-e51.
doi:10.1016/j.ijcard.2013.11.113
PMCID: PMC4116686  PMID: 24365613
Exercise; Breast cancer; Autonomic function; Cardiovascular disease; Cardiotoxicity
5.  Infective endocarditis in the Lao PDR: Clinical characteristics and outcomes in a developing country 
Introduction
Data on infective endocarditis (IE) in Southeast Asia are scarce.
Objectives
To describe the clinical epidemiology of IE in Lao PDR, a lower middle-income country.
Methods
A single centre retrospective study at Mahosot Hospital, Vientiane. Patients aged over 1 year of age admitted 2006–2012 to Mahosot Hospital with definite or possible IE by modified Duke criteria were included.
Results
Thirty-six patients fulfilled the inclusion criteria; 33 (91.7%) had left-sided IE. Eleven (30.6%) had definite IE and 25 (69.4%) possible left-sided IE. Median age was 25 years old [IQR 18–42]. Fifteen patients (41.7%) were males. Underlying heart diseases included: rheumatic valve disease in 12 (33.3%), congenital heart disease in 7 (19.4%), degenerative valve disease in 3 (8.3%), and of unknown origin in 14 (38.9%) patients. Native valve IE was present in 30 patients (83.3%), and prosthetic valve IE in 6 patients (16.7%). The most frequent pathogens were Streptococcus spp. in 7 (19.4%). Blood cultures were negative in 22 patients (61.1%). Complications included: heart failure in 11 (30.6%), severe valve regurgitation in 7 (19.4%); neurological event in 7 (19.4%); septic shock or severe sepsis in 5 (13.9%); and cardiogenic shock in 3 patients (8.3%). No patient underwent heart surgery. Fourteen (38.9%) had died by follow-up after a median of 2.1 years [IQR 1–3.2]; and 3 (8.3%) were lost to follow-up.
Conclusions
Infective endocarditis, a disease especially of young adults and mainly caused by Streptococcus spp., was associated with rheumatic heart disease and had high mortality in Laos.
Highlights
•Data on infective endocarditis (IE) in Southeast Asia are scarce. Most reports on IE originate from tertiary centres in Europe and North America and may not reflect the world's epidemiology of IE.•In Laos, IE remains a disease of young adults with no comorbidities, mainly caused by Streptococcus spp., associated with rheumatic heart disease.•Access to imaging techniques is limited and over half the patients have negative blood cultures.•Cardiac surgery is not routinely used in Laos for acute IE.•Mortality at 2 years follow-up is unacceptably high reaching 39%.
doi:10.1016/j.ijcard.2014.11.184
PMCID: PMC4323144  PMID: 25482077
Infective endocarditis; Rheumatic heart disease; Septicemia; Heart valve disease; Developing countries; Laos; Lao PDR
6.  Aspirin-triggered 15-epi-lipoxin A4 signals through FPR2/ALX in vascular smooth muscle cells and protects against intimal hyperplasia after carotid ligation 
doi:10.1016/j.ijcard.2014.11.010
PMCID: PMC4274317  PMID: 25464488
Lipoxin; Resolution of inflammation; Intimal hyperplasia; Smooth muscle cells
7.  Effect of Inhaled Iloprost on the Exercise Function of Fontan Patients 
International journal of cardiology  2013;168(3):2435-2440.
Background
Exercise capacity following Fontan surgery is often depressed. An inability to reduce pulmonary vascular resistance appropriately during exercise may contribute to this phenomenon. The aim of this study was to determine whether administration of iloprost, a selective pulmonary vasodilator, would improve exercise function after Fontan procedure.
Methods
Double-blind, randomized, placebo controlled, crossover trial. Patients performed two cardiopulmonary exercise tests (CPX) separated by <1 month. A single nebulizer treatment (iloprost or placebo) was administered before each CPX.
Results
18 patients aged 12–49 (median 17) yrs were recruited. Mild throat discomfort developed in 10/18 patients during iloprost administration; all but 1 were able to complete treatment. No symptoms developed during placebo treatments (p<0.001). Two additional patients did not complete CPX: one with atrial flutter; another with developmental issues that precluded adequate CPX. In the 15 remaining subjects oxygen pulse (a surrogate for forward stroke volume) at peak exercise was higher following iloprost (median increase 1.2 ml/beat; p<0.001). Peak VO2 also rose (median increase 1.3 ml/kg/min; p<0.04). Nine patients had peak VO2 <30 ml/kg/min; each of these patients had higher peak VO2 following iloprost. Only 3/6 patients with peak VO2 >30 ml/kg/min had higher peak VO2 following iloprost (p<0.04).
Conclusions
Iloprost improves the peak oxygen pulse and peak VO2 of patients with Fontan physiology and appears to be particularly beneficial among patients with impaired exercise function. Treatment is associated with minor side effects. These findings support the concept of pulmonary vasodilator therapy in Fontan patients with limited functional capacity.
doi:10.1016/j.ijcard.2013.03.014
PMCID: PMC4288936  PMID: 23545150
Fontan procedure; heart defects; congenital; exercise testing; vasodilation
8.  Syndrome of Severe Pain Associated with a Continuous Bumetanide Infusion 
International journal of cardiology  2014;177(2):e61-e62.
doi:10.1016/j.ijcard.2014.09.160
PMCID: PMC4283470  PMID: 25304072
Diuretics; adverse effect; allodynia; heart failure
9.  Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model☆ 
International Journal of Cardiology  2014;177(2):423-428.
Background
Macitentan is a new endothelin receptor antagonist that is used to treat pulmonary arterial hypertension in humans. Treatment of established pulmonary hypertension with macitentan was studied using the monocrotaline model of pulmonary hypertension.
Methods
Three groups of rats were created (n = 12): control (CON: macitentan only), monocrotaline (MCT: monocrotaline only) and macitentan (MACI: macitentan and monocrotaline). Monocrotaline (60 mg/kg) was injected in the MCT and MACI groups on day 0; volume matched saline was injected in the CON groups. Macitentan therapy (30 mg/kg/day) was commenced on day 11 in the CON and MACI groups. Serial echocardiography and ECGs were performed. The rats were sacrificed if they showed clinical deterioration.
Results
The MCT and MACI rats showed signs of pulmonary hypertension by day 7 (maximum pulmonary velocity, CON 1.15 ± 0.15 m/s vs MCT 1.04 ± 0.10 m/s vs MACI 0.99 ± 0.18 m/s; p < 0.05). Both the MCT and MACI groups developed pulmonary hypertension, but this was less severe in the MACI group (day 21 pulmonary artery acceleration time, MCT 17.55 ± 1.56 ms vs MACI 22.55 ± 1.00 ms; pulmonary artery deceleration, MCT 34.72 ± 3.72 m/s2 vs MACI 17.30 ± 1.89 m/s2; p < 0.05). Right ventricular hypertrophy and QT interval increases were more pronounced in MCT than MACI (right ventricle wall thickness, MCT 0.13 ± 0.1 cm vs MACI 0.10 ± 0.1 cm; QT interval, MCT 85 ± 13 ms vs MACI 71 ± 14 ms; p < 0.05). Survival benefit was not seen in the MACI group (p = 0.50).
Conclusions
Macitentan treatment improves haemodynamic parameters in established pulmonary hypertension. Further research is required to see if earlier introduction of macitentan has greater effects.
Highlights
•Monocrotaline administration caused pulmonary hypertension in rats.•Macitentan treatment delayed the progression of established pulmonary hypertension.•Macitentan treatment reduced right ventricular hypertrophy.•Macitentan treatment reduced QT interval prolongation.•Macitentan treatment caused no adverse events in the control group.
doi:10.1016/j.ijcard.2014.09.005
PMCID: PMC4251701  PMID: 25305681
Pulmonary arterial hypertension; Pulmonary hypertension; Macitentan; Echocardiogram; ECG; Monocrotaline
10.  Synergistic Effect of Local Endothelial Shear Stress and Systemic Hypercholesterolemia on Coronary Atherosclerotic Plaque Progression and Composition in Pigs 
International journal of cardiology  2013;169(6):394-401.
Background
Systemic risk factors and local hemodynamic factors both contribute to coronary atherosclerosis, but their possibly synergistic inter-relationship remains unknown. The purpose of this natural history study was to investigate the combined in-vivo effect of varying levels of systemic hypercholesterolemia and local endothelial shear stress (ESS) on subsequent plaque progression and histological composition.
Methods
Diabetic, hyperlipidemic swine with higher systemic total cholesterol (TC) (n=4) and relatively lower TC levels (n=5) underwent three-vessel intravascular ultrasound (IVUS) at 3–5 consecutive time-points in-vivo. ESS was calculated serially using computational fluid dynamics. 3-D reconstructed coronary arteries were divided into 3mm-long segments (n=595), which were stratified according to higher vs. relatively lower TC and low (<1.2 Pa) vs. higher local ESS (≥1.2 Pa). Arteries were harvested at 9 months, and a subset of segments (n=114) underwent histopathologic analyses.
Results
Change of plaque volume (ΔPV) by IVUS over time was most pronounced in low-ESS segments from higher-TC animals. Notably, higher-ESS segments from higher-TC animals had greater ΔPV compared to low-ESS segments from lower-TC animals (p<0.001). The time-averaged ESS in segments that resulted in significant plaque increased with increasing TC levels (slope: 0.24 Pa/100mg/dl; r=0.80; p<0.01). At follow-up, low-ESS segments from higher-TC animals had the highest mRNA levels of lipoprotein receptors and inflammatory mediators and, consequently, the greatest lipid accumulation and inflammation.
Conclusions
This study redefines the principle concept that “low” ESS promotes coronary plaque growth and vulnerability by demonstrating that: (i.) the pro-atherogenic threshold of low ESS is not uniform, but cholesterol-dependent; and (ii.) the atherogenic effects of local low ESS are amplified, and the athero-protective effects of higher ESS may be outweighed, by increasing cholesterol levels. Intense hypercholesterolemia and very low ESS are synergistic in favouring rapid atheroma progression and high-risk composition.
doi:10.1016/j.ijcard.2013.10.021
PMCID: PMC4191915  PMID: 24148915
coronary atherosclerosis; endothelial shear stress; hypercholesterolemia; intravascular ultrasound; histology
11.  The Association of Posttraumatic Stress Disorder and Quality of Life During the First Year after Acute Coronary Syndrome 
International journal of cardiology  2014;176(3):1042-1043.
doi:10.1016/j.ijcard.2014.07.290
PMCID: PMC4222037  PMID: 25149405
acute coronary syndrome; myocardial infarction; cardiovascular disease; posttraumatic stress disorder; quality of life; outcomes
12.  Childhood Lifestyle and Clinical Determinants of Adult Ideal 
International journal of cardiology  2013;169(2):10.1016/j.ijcard.2013.08.090.
Background
The American Heart Association recently defined ideal cardiovascular health by simultaneous presence of seven health behaviors and factors. The concept is associated with cardiovascular disease incidence, and cardiovascular disease and all-cause mortality. To effectively promote ideal cardiovascular health already early in life, childhood factors predicting future ideal cardiovascular health should be investigated. Our aim was thus to comprehensively explore childhood determinants of adult ideal cardiovascular health in population based cohorts from three continents.
Methods
The sample comprised a total of 4409 participants aged 3–19 years at baseline from the Cardiovascular Risk in Young Finns Study (YFS; N=1883) from Finland, Childhood Determinants of Adult Health Study (CDAH; N=1803) from Australia and Princeton Follow-up Study (PFS; N=723) from the United States. Participants were re-examined 19–31 years later when aged 30–48 years.
Results
In multivariable analyses, independent childhood predictors of adult ideal cardiovascular health were family socioeconomic status (P<0.01; direct association) and BMI (P<0.001; inverse association) in all cohorts. In addition, blood pressure (P=0.007), LDL-cholesterol (P<0.001) and parental smoking (P=0.006) in the YFS, and own smoking (P=0.001) in CDAH were inversely associated with future ideal cardiovascular health.
Conclusions
Among several lifestyle and clinical indicators studied, higher family socioeconomic status and non-smoking (parental/own) in childhood independently predict ideal cardiovascular health in adulthood. As atherosclerotic cardiovascular diseases are rooted in childhood, our findings suggest that special attention could be paid to children who are from low socioeconomic status families, and who smoke or whose parents smoke, to prevent cardiovascular disease morbidity and mortality.
doi:10.1016/j.ijcard.2013.08.090
PMCID: PMC3863693  PMID: 24075574
children; cardiovascular diseases; epidemiology; risk factors; prevention
13.  Associations between DSM-IV mental disorders and subsequent heart disease onset: beyond depression 
International journal of cardiology  2013;168(6):10.1016/j.ijcard.2013.08.012.
Background
Prior studies on the depression-heart disease association have not usually used diagnostic measures of depression, nor taken other mental disorders into consideration. As a result, it is not clear whether the association between depression and heart disease onset reflects a specific association, or the comorbidity between depression and other mental disorders. Additionally, the relative magnitude of associations of a range of mental disorders with heart disease onset is unknown.
Methods
Face-to-face household surveys were conducted in 19 countries (n=52,095; person years=2,141,194). The Composite International Diagnostic Interview retrospectively assessed lifetime prevalence and age at onset of 16 DSM-IV mental disorders. Heart disease was indicated by self-report of physician’s diagnosis, or self-report of heart attack, together with their timing (year). Survival analyses estimated associations between first onset of mental disorders and subsequent heart disease onset.
Results
After comorbidity adjustment, depression, panic disorder, specific phobia, post-traumatic stress disorder and alcohol use disorders were associated with heart disease onset (ORs 1.3–1.6). Increasing number of mental disorders was associated with heart disease in a dose-response fashion. Mood disorders and alcohol abuse were more strongly associated with earlier onset than later onset heart disease. Associations did not vary by gender.
Conclusions
Depression, anxiety and alcohol use disorders were significantly associated with heart disease onset; depression was the weakest predictor. If confirmed in future prospective studies, the breadth of psychopathology’s links with heart disease onset has substantial clinical and public health implications.
doi:10.1016/j.ijcard.2013.08.012
PMCID: PMC3886238  PMID: 23993321
depression; anxiety disorders; alcohol abuse; heart disease; comorbidity
14.  Impact of aldosterone antagonists on the substrate for atrial fibrillation: Aldosterone promotes oxidative stress and atrial structural/electrical remodeling 
International journal of cardiology  2013;168(6):5135-5142.
Atrial fibrillation (AF), the most common cardiac arrhythmia, is an electrocardiographic description of a condition with multiple and complex underlying mechanisms. Oxidative stress is an important driver of structural remodeling that creates a substrate for AF. Oxidant radicals may promote increase of atrial oxidative damage, electrical and structural remodeling, and atrial inflammation. AF and other cardiovascular morbidities activate angiotensin (Ang-II)-dependent and independent cascades. A key component of the renin–angiotensin-aldosterone system (RAAS) is the mineralocorticoid aldosterone. Recent studies provide evidence of myocardial aldosterone synthesis. Aldosterone promotes cardiac oxidative stress, inflammation and structural/electrical remodeling via multiple mechanisms. In HF patients, aldosterone production is enhanced. In patients and in experimental HF and AF models, aldosterone receptor antagonists have favorable influences on cardiac remodeling and oxidative stress. Therapeutic approaches that seek to reduce AF burden by modulating the aldosterone system are likely beneficial but underutilized.
doi:10.1016/j.ijcard.2013.08.022
PMCID: PMC4062912  PMID: 23993726
Aldosterone; Aldosterone antagonist; Atrial fibrillation; Oxidative stress
15.  MicroRNA Associated with Atherogenic Dyslipidemia in South Asian Men 
International journal of cardiology  2013;168(5):10.1016/j.ijcard.2013.07.029.
doi:10.1016/j.ijcard.2013.07.029
PMCID: PMC3809319  PMID: 23871617
microRNA; cholesterol; lipids; lipoproteins; cardiovascular risk; South Asian
16.  Physical Activity is Associated with Improved Aerobic Exercise Capacity over Time in Adults with Congenital Heart Disease 
International journal of cardiology  2013;168(5):10.1016/j.ijcard.2013.07.177.
Background
Impaired exercise capacity is common in adults with congenital heart disease (ACHD). This impairment is progressive and is associated with increased morbidity and mortality. We studied the influence of the frequency of at least moderately strenuous physical activity (PhysAct) on changes in exercise capacity of ACHD patients over time.
Methods
We studied ACHD patients ≥21 years old who had repeated maximal (RER≥1.09) cardiopulmonary exercise tests within 6 to 24 months. On the basis of data extracted from each patient’s clinical records, PhysAct frequency was classified as (1) Low: minimal PhysAct, (2) Occasional: moderate PhysAct <2 times/week, or (3) Frequent: moderate PhysAct ≥2 times/week.
Results
PhysAct frequency could be classified for 146 patients. Those who participated in frequent exercise tended to have improved pVO2 (ΔpVO2=+1.63±2.67 ml/kg/min) compared to those who had low or occasional activity frequency (ΔpVO2=+0.06±2.13 ml/kg/min, p=0.003) over a median follow-up of 13.2 months. This difference was independent of baseline clinical characteristics, time between tests, medication changes, or weight change. Those who engaged in frequent PhysAct were more likely to have an increase of pVO2 of ≥1SD between tests as compared with sedentary patients (multivariable OR=7.4, 95%CI 1.5-35.7). Aerobic exercise capacity also increased for patients who increased activity frequency from baseline to follow-up; 27.3% of those who increased their frequency of moderately strenuous physical activity had a clinically significant (at least +1SD) increase in pVO2 compared to only 11% of those who maintained or decreased activity frequency.
Conclusions
ACHD patients who engage in frequent physical activity tend to have improved exercise capacity over time.
doi:10.1016/j.ijcard.2013.07.177
PMCID: PMC3809326  PMID: 23962775
congenital heart disease; adults; exercise capacity and physical activity
17.  Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension 
International journal of cardiology  2013;168(5):4643-4651.
Background
Substance P is a sensory nerve neuropeptide located near coronary vessels in the heart. Therefore, substance P may be one of the first mediators released in the heart in response to hypertension, and can contribute to adverse myocardial remodeling via interactions with the neurokinin-1 receptor. We asked: 1) whether substance P promoted cardiac hypertrophy, including the expression of fetal genes known to be re-expressed during pathological hypertrophy; and 2) the extent to which substance P regulated collagen production and fibrosis.
Methods and Results
Spontaneously hypertensive rats (SHR) were treated with the neurokinin-1 receptor antagonist L732138 (5 mg/kg/d) from 8 to 24 weeks of age. Age-matched WKY served as controls. The gene encoding substance P, TAC1, was up-regulated as blood pressure increased in SHR. Fetal gene expression by cardiomyocytes was increased in SHR and was prevented by L732138. Cardiac fibrosis also occurred in the SHR and was prevented by L732138. Endothelin-1 was up-regulated in the SHR and this was prevented by L732138. In isolated cardiac fibroblasts, substance P transiently up-regulated several genes related to cell-cell adhesion, cell-matrix adhesion, and extracellular matrix regulation, however, no changes in fibroblast function were observed.
Conclusions
Substance P activation of the neurokinin-1 receptor induced expression of fetal genes related to pathological hypertrophy in the hypertensive heart. Additionally, activation of the neurokinin-1 receptor was critical to the development of cardiac fibrosis. Since no functional changes were induced in isolated cardiac fibroblasts by substance P, we conclude that substance P mediates fibrosis via up-regulation of endothelin-1.
doi:10.1016/j.ijcard.2013.07.190
PMCID: PMC4043399  PMID: 23962787
Hypertrophy; fetal genes; fibrosis; substance P; cardiac fibroblast
18.  Distinctive Profile of Sudden Cardiac Arrest in Middle-Aged vs. Older Adults: A Community-Based Study 
International journal of cardiology  2013;168(4):3495-3499.
Background
While sudden cardiac arrest (SCA) rates increase with age, middle-aged adults (35–59 years) may comprise a significant proportion of SCA cases in the community (30–40%). However, there is a lack of studies evaluating SCA risk factors specifically associated with this age-group of the population.
Methods
Using prospective multiple-source surveillance methodology we identified cases of SCA ≥35 years in the ongoing Oregon Sudden Unexpected Death Study (Portland, Oregon metropolitan area, population ≈1,000,000). Out-of-hospital SCA cases, aged 35–59 years were compared to older SCA cases (≥60years) in a comprehensive analysis of clinical profile of SCA.
Results
The middle-aged (n=753) compared to older (n=1251) cases were more likely to be male, obese, have sleep apnea and seizure disorder (all p≤0.001); and were less likely to have a history of hypertension, diabetes mellitus, known coronary artery disease, congestive heart failure and syncope (all p<0.01). In multivariable analyses the middle-aged group had higher likelihood of male sex (O.R. 1.67, 95% C.I. 1.29–2.18), obesity (2.20, 1.52–3.19), sleep apnea (2.30, 1.44–3.68) and seizure disorder (2.69, 1.64–4.42); and lower rates of known coronary artery disease (0.57, 0.43–0.74) and congestive heart failure (0.35, 0.25–0.48).
Conclusions
SCA in the middle-aged adult was distinguishable from older subjects by higher rates of obesity, sleep apnea and seizure disorder; and lower prevalence of traditional clinical risk markers. With the growing epidemic of obesity, these findings have implications for SCA burden; and suggest the need for a clinical and investigational focus on SCA prediction and prevention in the middle-aged adult, that is distinct from older adults.
doi:10.1016/j.ijcard.2013.04.207
PMCID: PMC3779526  PMID: 23684602
sudden-death; obesity; coronary artery disease; middle-age; community
19.  Protein-L-isoaspartate (D-aspartate) O-Methyltransferase Protects Cardiomyocytes Against Hypoxia Induced Apoptosis Through Inhibiting Proapoptotic Kinase Mst1 
International journal of cardiology  2013;168(4):3291-3299.
Background
Mammalian sterile 20-like kinase 1 (Mst1) is a mammalian homolog of Hippo kinase from Drosophila and it is a critical component of the Hippo signaling pathway, which regulates a variety of biological processes ranging from cell contact inhibition, organ size control, apoptosis and tumor suppression in mammals. Mst1 plays essential roles in the heart disease since its activation causes cardiomyocyte apoptosis and dilated cardiomyopathy. However, the mechanism underlying Mst1 activation in the heart is not known.
Methods and Results
To identify novel cardiac proteins that may regulate Mst1 activity in the heart under pathophysiological conditions, a yeast two-hybrid screen of a human heart cDNA library with a dominant-negative Mst1 (K59R) mutant used as bait was performed. As a result, protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) was identified as an Mst1-interacting protein. The interaction of PCMT1 with Mst1 was confirmed by co-immunoprecipitation in both co-transfected HEK293 cells and native cardiomyocytes, in which PCMT1 interacted with the kinase domain of Mst1, but not with its C-terminal regulatory domain. Overexpression of PCMT1 did not affect the Mst1 expression, but significantly attenuated the Mst1 activation and its apoptotic effects in response to the hypoxia/reoxygenation induced injury in cardiomyocytes. Indeed, upregulation of PCMT1 by CGP3466B, a compound related to the anti-Parkinson’s drug R-(−)-deprenyl with potent antiapoptotic effects, inhibited the hypoxia/reoxygenation induced Mst1 activation and cardiomyocte apoptosis.
Conclusions
These findings implicate PCMT1 as a novel inhibitor of Mst1 activation in cardiomyocytes and suggest that targeting PCMT1 may prevent myocardial apoptosis through inhibition of Mst1.
doi:10.1016/j.ijcard.2013.04.045
PMCID: PMC3788851  PMID: 23647599
Mst1 kinase; PCMT1; hypoxia/reoxygenation; cardiac myocytes; apoptosis
20.  (−)-Epicatechin rich cocoa mediated modulation of oxidative stress regulators in skeletal muscle of heart failure and type 2 diabetes patients 
International journal of cardiology  2013;168(4):3982-3990.
Background
Type 2 diabetes (T2D) and heart failure (HF) are associated with high levels of skeletal muscle (SkM) oxidative stress (OS). Health benefits attributed to flavonoids have been ascribed to antioxidation. However, for flavonoids with similar antioxidant potential, end-biological effects vary widely suggesting other mechanistic venues for reducing OS. Decreases in OS may follow the modulation of key regulatory pathways including antioxidant levels (e.g. glutathione) and enzymes such as mitochondrial superoxide dismutase (SOD2) and catalase.
Methods
We examined OS-related alterations in SkM in T2D/HF patients (as compared vs. healthy controls) and evaluated the effects of three-month treatment with (−)-epicatechin (Epi) rich cocoa (ERC). To evidence Epi as the mediator of the improved OS profile we examined the effects of pure Epi (vs. water) on SkM OS regulatory systems in a mouse model of insulin resistance and contrasted results vs. normal mice.
Results
There were severe alterations in OS regulatory systems in T2D/HF SkM as compared with healthy controls. Treatment with ERC induced recovery in glutathione levels and decreases in the nitrotyrosilation and carbonylation of proteins. With treatment, key transcriptional factors translocate into the nucleus leading to increases in SOD2 and catalase protein expression and activity levels. In insulin resistant mice, there were alterations in muscle OS and pure Epi replicated the beneficial effects of ERC found in humans.
Conclusions
Major perturbations in SkM OS can be reversed with ERC in T2D/HF patients. Epi likely mediates such effects and may provide an effective means to treat conditions associated with tissue OS.
doi:10.1016/j.ijcard.2013.06.089
PMCID: PMC3805662  PMID: 23870648
epicatechin; cocoa; flavanols
21.  Features of portal hypertension are associated with major adverse events in Fontan patients: The VAST study 
International journal of cardiology  2013;168(4):3764-3769.
Background
Chronic congestive hepatopathy is known to cause hepatic fibrosis and portal hypertension in patients post-Fontan operation for single ventricle palliation. The clinical significance of these findings is not clear. We hypothesized that features of portal hypertension would be significantly related to major adverse events.
Methods
A retrospective review of 73 adult and pediatric post-Fontan patients referred for a liver evaluation from 2001-2011 was performed. The relationship between features of portal hypertension (VAST score ≥2, 1 point each for Varices, Ascites, Splenomegaly or Thrombocytopenia) and a major adverse event (death, need for transplant, or hepatocellular carcinoma) was examined using logistic regression.
Results
73 post-Fontan patients (30% female, 73% Caucasian, 66% systemic left ventricle (SLV), mean age 24 ±11 years, mean interval from Fontan 17 ±6 years) were included in analysis. Features of portal hypertension (VAST score ≥2) were present in 26 (36%), and there were 19 major adverse events: death (n=12), transplant (n=6), HCC (n=1). A significant relationship was found between VAST score ≥2 and major adverse events (OR=9.8, 95% CI [2.9-32.7]). After adjusting for time since Fontan, SLV, age, hemoglobin and type of failure, VAST score ≥2 remained significant (OR=9.1, 95% CI [1.4-57.6]).
Conclusion
Fontan patients with features of portal hypertension have a 9-fold increased risk for a major adverse event. Therapies targeted to manage clinical manifestations of portal hypertension, and early referral to heart transplant may help delay major adverse events. Future prospective studies are needed to confirm these findings.
doi:10.1016/j.ijcard.2013.06.008
PMCID: PMC3805740  PMID: 23849105
Fontan; liver disease; features of portal hypertension; congenital heart disease; adult congenital heart disease
22.  Perivascular Fat, Inflammation, and Cardiovascular Risk in HIV-infected Patients on Antiretroviral Therapy 
International journal of cardiology  2013;168(4):4039-4045.
Background
HIV-infection is characterized by chronic immune activation that persists despite effective antiretroviral therapy (ART) and is associated with elevated cardiovascular risk. Whether specific perivascular fat depots are associated with inflammation in HIV is unknown.
Methods
In a cross-sectional study, epicardial (EAT) and thoracic periaortic (TAT) adipose tissue volume were measured by computed tomography in 100 HIV-infected adults, on stable ART, with LDL-cholesterol ≤130mg/dL and evidence of heightened T-cell activation (CD8+CD38+HLA−DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2mg/L).
Results
Overall, 77% were male and 70% African American. Mean (standard deviation) age and body mass index were 47 (10) years and 28 (6.4) kg/m2, respectively. All subjects had HIV-1 RNA <1,000 copies/mL with mean (standard deviation) CD4+ T cell count of 665 (280) cells/μL; 50% were on a protease inhibitor. EAT and TAT were correlated with each other (r=0.766, p<0.0001). Both were associated with metabolic syndrome, atherogenic lipid profile, insulin resistance, total and central body fat, serum biomarkers of inflammation, and soluble CD163, but not with cellular immune activation markers. In multivariable models that adjusted for age, sex, and other measures of adiposity, both perivascular fat depots were independently associated with the presence of coronary calcium.
Conclusions
Perivascular fat is associated with soluble CD163, biomarkers of inflammation, insulin resistance, and subclinical atherosclerosis in this population of virologically suppressed HIV-infected patients on ART. The association of perivascular fat with coronary artery calcification appears to be independent of other measures of adiposity.
doi:10.1016/j.ijcard.2013.06.059
PMCID: PMC3805774  PMID: 23886531
Adipose tissue; Atherosclerosis; HIV; Inflammation; Macrophages
23.  Relationship of CRP, IL-6, and Fibrinogen with Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
International journal of cardiology  2013;168(4):3818-3824.
Background/objectives
Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited.
Methods and results
The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4,009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses.
Conclusion
Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.
doi:10.1016/j.ijcard.2013.06.028
PMCID: PMC3805818  PMID: 23932860
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
24.  Angiotensin Type 2 Receptors in the Intermediolateral Cell Column of the Spinal Cord: Negative Regulation of Sympathetic Nerve Activity and Blood Pressure 
International journal of cardiology  2013;168(4):10.1016/j.ijcard.2013.06.051.
BACKGROUND
Our previous study demonstrated that AT2R in brainstem nuclei participated in the regulation of sympathetic outflow and cardiovascular function. However, the functional significance of AT2R in the intermediolateral cell column (IML) of the thoracic spinal cord in normal rats remains elusive. We hypothesized that AT2R activation in the IML exert a sympatho-inhibitory effect.
METHODS and RESULTS
Using Western-blot analysis, immunohistochemical staining and quantitative Real-Time PCR, both AT1R and AT2R expression were detected in the spinal cord. The highest AT2R protein expression was found in the IML, while AT1R expression didn’t display regional differences within the gray matter. Microinjection of AngII into the IML dose-dependently elevated mean blood pressure (MAP, employing a transducer-tipped catheter) and renal sympathetic nerve activity (RSNA, using a pair of platinum-iridium recording electrodes), which was completely abolished by Losartan, and attenuated by TEMPOL and apocynin. Activation of AT2R in the IML with CGP42112 evoked hypotension (ΔMAP: −21 ± 4 mmHg) and sympatho-inhibition (RSNA: 73 ± 3% of baseline), which were completely abolished by PD123319 and L-NAME. Blockade of AT2R in the IML with PD123319 significantly increased MAP (11 ± 1 mmHg) and sympathetic nerve activity (RSNA: 133 ± 13 % of baseline). Moreover, PD123319 significantly enhanced the AngII induced pressor response. Furthermore, in isolated IML neurons, CGP42112 treatment augmented potassium current and decreased resting membrane potential by employing whole-cell patch clamp.
Conclusion
In the normal condition, AT2R in the IML tonically inhibit sympathetic activity through an NO/NOS dependent pathway and subsequent potassium channel activation.
doi:10.1016/j.ijcard.2013.06.051
PMCID: PMC3821163  PMID: 23871345
Intermediolateral cell column; Angiotensin type 1 receptor; Angiotensin type 2 receptor; arterial blood pressure; renal sympathetic nerve activity
25.  Cardiac autonomic control in Brugada patients during sleep: the effects of sleep disordered breathing 
International journal of cardiology  2013;168(4):10.1016/j.ijcard.2013.04.137.
Aims
Brugada syndrome is characterized by typical ECG features, ventricular arrhythmias and sudden cardiac death (SCD), more frequent during nighttime. Autonomic cardiovascular control has been implicated in triggering the ventricular arrhythmias. Sleep-disordered breathing (SDB) elicits marked autonomic changes during sleep and it is associated with an increased risk of nighttime SCD. Brugada patients may have a higher likelihood of SDB compared to controls. However, no data are available on cardiac autonomic control in Brugada patients, particularly with regard to the comorbidity of SDB.
Methods
We evaluated autonomic cardiovascular control in Brugada patients with SDB (BRU-SDB, n=9), without SDB (BRU, n= 9), in controls (CON, n=8) and in non-Brugada patients with SDB (n=6), during wakefulness and sleep (N2, N3 and REM). Linear spectral and entropy-derived measures of heart rate variability (HRV) were performed during apnea-free stable breathing epochs.
Results
Total HRV was attenuated in BRU-SDB compared to CON and BRU. During N2 and REM, in BRU-SDB patients sympathetic modulation decreased compared to BRU and CON, while during REM, they showed an increased parasympathetic modulation, compared to the other two groups. BRU-SDB and SDB were similar in terms of spectral components. Entropy-derived indices showed preserved dynamic changes in Brugada patients compared to controls through the different sleep stages.
Conclusion
Brugada syndrome per se does not appear associated with an altered autonomic cardiovascular control during wakefulness and sleep. The comorbidity with SDB may contribute to disrupted autonomic cardiovascular regulation during sleep, possibly predisposing to the increased likelihood of sleep-related ventricular tachyarrhythmias and SCD.
doi:10.1016/j.ijcard.2013.04.137
PMCID: PMC3851035  PMID: 23669108
Brugada syndrome; sleep disordered breathing; heart rate variability; non linear analysis; sleep; autonomic nervous system

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