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1.  MASP-2 Activation is Involved in Ischemia-related Necrotic Myocardial Injury in Humans 
International journal of cardiology  2011;166(2):499-504.
Background/Objectives
Insufficient blood supply to the heart results in ischemic injury manifested clinically as myocardial infarction (MI). Following ischemia, inflammation is provoked and related to the clinical outcomes. A recent basic science study indicates that complement factor MASP-2 plays an important role in animal models of ischemia/reperfusion injury. We investigated the role of MASP-2 in human acute myocardial ischemia in two clinical settings: (1) Acute MI, and (2) Open heart surgery.
Methods
A total of 187 human subjects were enrolled in this study, including 50 healthy individuals, 27 patients who were diagnosed of coronary artery disease (CAD) but without acute MI, 29 patients with acute MI referred for coronary angiography, and 81 cardiac surgery patients with surgically-induced global heart ischemia. Circulating MASP-2 levels were measured by ELISA.
Results
MASP-2 levels in the peripheral circulation were significantly reduced in MI patients compared with those of healthy individuals or of CAD patients without acute MI. The hypothesis that MASP-2 was activated during acute myocardial ischemia was evaluated in cardiac patients undergoing surgically-induced global heart ischemia. MASP-2 was found to be significantly reduced in the coronary circulation of such patients, and the reduction of MASP-2 levels correlated independently with the increase of the myocardial necrosis marker, cardiac troponin I.
Conclusions
These results indicate an involvement of MASP-2 in ischemia-related necrotic myocardial injury in humans.
doi:10.1016/j.ijcard.2011.11.032
PMCID: PMC3310957  PMID: 22178059
MASP-2; myocardial ischemia; necrosis
3.  2014 Global geographic analysis of mortality from ischaemic heart disease by country, age and income: Statistics from World Health Organisation and United Nations 
International Journal of Cardiology  2014;174(2):293-298.
Background
Ischaemic heart disease (IHD) is the leading cause of death worldwide and its prevention is a public health priority.
Method
We analysed worldwide IHD mortality data from the World Health Organisation as of February 2014 by country, age and income. Age-standardised mortality rates by country were calculated. We constructed a cartogram which is an algorithmically transformed world map that conveys numbers of deaths in the form of spatial area.
Results
Of the countries that provided mortality data, Russia, the United States of America and Ukraine contributed the largest numbers of deaths. India and China were estimated to have even larger numbers of deaths. Death rates from IHD increase rapidly with age. Crude mortality rates appear to be stable whilst age-standardised mortality rates are falling. Over half of the world's countries (113/216) have provided IHD mortality data for 2008 or later. Of these, 13 countries provided data in 2012. No countries have yet provided 2013 data. Of the 103 remaining countries, 24 provided data in 2007 or earlier, and 79 have never provided data in the ICD9 or ICD10 format.
Conclusions
In the countries for which there are good longitudinal data, predominantly European countries, recent years have shown a continuing decline in age-standardised IHD mortality. However, the progressive aging of populations has kept crude IHD mortality high. It is not known whether the pattern is consistent globally because many countries have not provided regular annual data including wealthy countries such as the United Arab Emirates and large countries such as India and China.
Highlights
•We use a cartogram to display the worldwide distribution of IHD deaths.•India, China, Russia, USA and Ukraine have the largest estimated numbers of deaths.•Turkmenistan and Ukraine have the highest estimated standardised mortality ratios.•Crude IHD mortality remains high whilst age-standardised mortality is falling.•Only 113 of 216 countries provided IHD mortality data for 2008 or later.
doi:10.1016/j.ijcard.2014.04.096
PMCID: PMC4045191  PMID: 24794549
Ischaemic heart disease; Coronary heart disease; Mortality; Cartogram
4.  Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data 
International journal of cardiology  2011;166(1):230-235.
Background
Heart failure (HF) is the leading cause of hospitalization for Medicare beneficiaries. Nearly half of all HF patients have diastolic HF or HF with preserved ejection fraction (HF-PEF). Because these patients were excluded from major randomized clinical trials of neurohormonal blockade in HF there is little evidence about their role in HF-PEF.
Methods
The aims of the American Recovery & Reinvestment Act-funded National Heart, Lung, and Blood Institute-sponsored “Neurohormonal Blockade and Outcomes in Diastolic Heart Failure” are to study the long-term effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists in four separate propensity-matched populations of HF-PEF patients in the OPTIMIZE-HF (Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure) registry. Of the 48,612 OPTIMIZE-HF hospitalizations occurring during 2003–2004 in 259 U.S. hospitals, 20,839 were due to HF-PEF (EF ≥40%). For mortality and hospitalization we used Medicare national claims data through December 31, 2008.
Results
Using a two-step (hospital-level and hospitalization-level) probabilistic linking approach, we assembled a cohort of 11,997 HF-PEF patients from 238 OPTIMIZE-HF hospitals. These patients had a mean age of 75 years, mean EF of 55%, were 62% women, 15% African American, and were comparable with community-based HF-PEF cohorts in key baseline characteristics.
Conclusions
The assembled Medicare-linked OPTIMIZE-HF cohort of Medicare beneficiaries with HF-PEF with long-term outcomes data will provide unique opportunities to study clinical effectiveness of various neurohormonal antagonists with outcomes in HF-PEF using propensity-matched designs that allow outcome-blinded assembly of balanced cohorts, a key feature of randomized clinical trials.
doi:10.1016/j.ijcard.2011.10.089
PMCID: PMC3465528  PMID: 22119116
Diastolic heart failure; neurohormonal antagonists; OPTIMIZE-HF; Medicare
5.  Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium 
International journal of cardiology  2012;166(1):246-248.
doi:10.1016/j.ijcard.2012.09.027
PMCID: PMC3646959  PMID: 23098852
polyphenol; biomarker; adhesion molecule; inflammation; insulin; red wine
6.  Regional imbalanced activation of the calcineurin/BAD apoptotic pathway and the PI3K/Akt survival pathway after myocardial infarction 
International journal of cardiology  2011;166(1):10.1016/j.ijcard.2011.10.107.
Background
The underlying molecular mechanisms of the remodeling after myocardial infarction (MI) remain unclear. The purpose of this study was to investigate the role of a survival pathway (PI3K/Akt) and an apoptosis pathway (calcineurin/BAD) in the remodeling after MI in a large animal model.
Methods
Ten Dorset hybrid sheep underwent 25% MI in the left ventricle (LV, n=10). Five sheep were used as sham control. The regional strain was calculated from sonomicrometry. Apoptosis and the activation of the PI3K/Akt and calcineurin/BAD pathways were evaluated in the non-ischemic adjacent zone and the remote zone relative to infarct by immunoblotting, immunoprecipitation, and immunofluorescence staining.
Results
Dilation and dysfunction of LV were present at 12 weeks after MI. The regional strain in the adjacent zone was significantly higher than in the remote zone at 12 weeks (36.6 ± 4.0% vs 9.5 ± 3.6%, p < 0.05). Apoptosis was more severe in the adjacent zone than in the remote zone. The PI3K/Akt and calcineurin/BAD pathways were activated in the adjacent zone. Dephosphorylation and translocation of BAD were evident in the adjacent zone. Regional correlation between the strain and the expression of calcineurin/BAD indicated that the activation was strain-related (R2 = 0.46, 0.48, 0.39 for calcineurin, BAD, mitochondrial BAD, respectively, p < 0.05).
Conclusions
The PI3K/Akt survival and calcineurin/BAD apoptotic pathways were concomitantly activated in the non-ischemic adjacent zone after MI. The calcineurin/BAD pathway is strain related and its imbalanced activation may be one of the causes of progressive remodeling after MI.
doi:10.1016/j.ijcard.2011.10.107
PMCID: PMC3303985  PMID: 22088220
Myocardial infarction; Remodeling; Strain; Apoptosis; calcineurin; BAD
7.  Association of myeloperoxidase with total and cardiovascular mortality in individuals undergoing coronary angiography—The LURIC study 
Background
The phagocytic enzyme myeloperoxidase (MPO) acts as a front-line defender against microorganisms. However, increased MPO levels have been found to be associated with complex and calcified atherosclerotic lesions and incident cardiovascular disease. Therefore, this study aimed to investigate a predictive role of MPO, a biomarker of inflammation and oxidative stress, for total and cardiovascular mortality in patients referred to coronary angiography.
Methods and results
MPO plasma concentrations along with eight MPO polymorphisms were determined in 3036 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up 7.75 years). MPO concentrations were positively associated with age, diabetes, smoking, markers of systemic inflammation (interleukin-6, fibrinogen, C-reactive protein, serum amyloid A) and vascular damage (vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1) but negatively associated with HDL-cholesterol and apolipoprotein A-I. After adjustment for cardiovascular risk factors MPO concentrations in the highest versus the lowest quartile were associated with a 1.34-fold risk (95% CI: 1.09–1.67) for total mortality. In the adjusted model the hazard ratio for cardiovascular mortality in the highest MPO quartile was 1.42 (95% CI: 1.07–1.88). Five MPO polymorphisms were positively associated with MPO concentrations but not with mortality. Using Mendelian randomization, we did not obtain evidence for a causal association of MPO with either total or cardiovascular mortality.
Conclusions
MPO concentrations but not genetic variants at the MPO locus are independently associated with risk for total and cardiovascular mortality in coronary artery disease patients.
doi:10.1016/j.ijcard.2014.03.168
PMCID: PMC4045190  PMID: 24746542
Myeloperoxidase; Inflammation; High-density lipoprotein; Cardiovascular mortality; Risk factor
8.  15-deoxy-Δ12,14-PGJ2 promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis 
International Journal of Cardiology  2014;173(3):472-480.
Background
Prostaglandins (PGs), lipid autacoids derived from arachidonic acid, play a pivotal role during inflammation. PGD2 synthase is abundantly expressed in heart tissue and PGD2 has recently been found to induce cardiomyocyte apoptosis. PGD2 is an unstable prostanoid metabolite; therefore the objective of the present study was to elucidate whether its final dehydration product, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2, present at high levels in ischemic myocardium) might cause cardiomyocyte damage.
Methods and results
Using specific (ant)agonists we show that 15d-PGJ2 induced formation of intracellular reactive oxygen species (ROS) and phosphorylation of p38 and p42/44 MAPKs via the PGD2 receptor DP2 (but not DP1 or PPARγ) in the murine atrial cardiomyocyte HL-1 cell line. Activation of the DP2-ROS-MAPK axis by 15d-PGJ2 enhanced transcription and translation of TNFα and induced apoptosis in HL-1 cardiomyocytes. Silencing of TNFα significantly attenuated the extrinsic (caspase-8) and intrinsic apoptotic pathways (bax and caspase-9), caspase-3 activation and downstream PARP cleavage and γH2AX activation. The apoptotic machinery was unaffected by intracellular calcium, transcription factor NF-κB and its downstream target p53. Of note, 9,10-dihydro-15d-PGJ2 (lacking the electrophilic carbon atom in the cyclopentenone ring) did not activate cellular responses. Selected experiments performed in primary murine cardiomyocytes confirmed data obtained in HL-1 cells namely that the intrinsic and extrinsic apoptotic cascades are activated via DP2/MAPK/TNFα signaling.
Conclusions
We conclude that the reactive α,β-unsaturated carbonyl group of 15d-PGJ2 is responsible for the pronounced upregulation of TNFα promoting cardiomyocyte apoptosis. We propose that inhibition of DP2 receptors could provide a possibility to modulate 15d-PGJ2-induced myocardial injury.
doi:10.1016/j.ijcard.2014.03.086
PMCID: PMC4008937  PMID: 24698234
Cardiomyocytes; TNFα; 15d-PGJ2; Apoptosis; PGD2 receptor
9.  Parity and Aortic Dimensions in Healthy Women 
International journal of cardiology  2012;165(2):383-384.
doi:10.1016/j.ijcard.2012.08.022
PMCID: PMC3532567  PMID: 22999343
Pregnancy; parity; aorta; magnetic resonance; aging
10.  Novel Deletion Mutation in the Cardiac Sodium Channel Inactivation Gate Causes Long QT Syndrome 
International journal of cardiology  2012;165(2):362-365.
doi:10.1016/j.ijcard.2012.08.032
PMCID: PMC3538169  PMID: 22980924
Long QT syndrome; sodium channel; cardiac arrhythmias; SCN5A; electrophysiology
12.  Cardiovascular biomarkers in acute Kawasaki disease 
Background
Endomycocardial biopsies have demonstrated that subclinical myocarditis is a universal feature of acute Kawasaki disease (KD).
Methods
We investigated biochemical evidence of myocardial strain, oxidative stress, and cardiomyocyte injury in 55 acute KD subjects (30 with paired convalescent samples), 54 febrile control (FC), and 50 healthy control (HC) children by measuring concentrations of cardiovascular biomarkers.
Results
Levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble ST2 (sST2) were elevated in acute vs. convalescent KD, FC, and HC (p≤0.0002), while γ-glutamyl transferase and alanine amino transferase as measures of oxidative stress were increased in acute vs. FC (p≤0.0008). Cardiac troponin I (cTnI) levels, using a highly sensitive assay, were elevated in 30% and 40% of paired acute and convalescent KD subjects, respectively, and normalized within two years of disease onset. NT-proBNP and sST2 negatively correlated with measures of diastolic function (MV E:A ratio and deceleration time), but only NT-proBNP positively correlated with the coronary artery Z score.
Conclusions
NT-proBNP and sST2 were elevated in acute KD subjects and correlated with impaired myocardial relaxation. These findings, combined with elevated levels of cTnI, suggest that both cardiomyocyte stress and cell death are associated with myocardial inflammation in acute KD.
doi:10.1016/j.ijcard.2011.06.065
PMCID: PMC3253177  PMID: 21777987
diastolic dysfunction; oxidative stress; myocarditis; coronary artery aneurysm
13.  Inhibition of Vein Graft Stenosis in Rabbits with a c-jun Targeting DNAzyme in a Cationic Liposomal Formulation Containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) 
International journal of cardiology  2013;168(4):3659-3664.
Background/Objectives
Coronary artery bypass grafting (CABG) is among the most commonly performed heart surgical procedures for the treatment of ischemic heart disease. Saphenous vein graft failure due to stenosis impedes the longer-term success of CABG. A key cellular event in the process of vein graft stenosis is smooth muscle cell (SMC) hyperplasia. In this study, we evaluated the effect of a DNAzyme (Dz13) targeting the transcription factor c-Jun in a rabbit model of vein graft stenosis after autologous transplantation in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Dz13 in DOTAP/DOPE has undergone preclinical toxicological testing, and a Phase I clinical trial we recently conducted in skin cancer patients demonstrates that it is safe and well tolerated after local administration.
Methods
Effects of Dz13 in a formulation containing DOTAP/DOPE on SMC growth and c-Jun expression were assessed. Dz13 transfection was determined by cellular uptake of carboxyfluorescein-labeled Dz13. Autologous jugular vein to carotid artery transplantation was performed in New Zealand White rabbits to investigate the effect of the Dz13 in DOTAP/DOPE formulation on the extent of intimal hyperplasia.
Results
Dz13/DOTAP/DOPE reduced SMC proliferation and c-Jun protein expression in vitro compared with an impotent form of Dz13 bearing a point mutation in its catalytic domain (Dz13.G>C). The Dz13 (500 µg)/DOTAP/DOPE formed lipoplexes that were colloidally stable for up to 1 hour on ice (0°C) or 30 minutes at 37°C, allowing sufficient uptake by the veins. Dz13 (500µg) inhibited neointima formation 28 days after end-to-side transplantation.
Conclusions
This formulation applied to veins prior to transplantation may potentially be useful in efforts to reduce graft failure.
doi:10.1016/j.ijcard.2013.05.092
PMCID: PMC3951723  PMID: 23886527
smooth muscle cells; intimal thickening; vein bypass graft; autologous end-to-side transplantation; gene silencing; bypass grafts
15.  Cardiac contractility modulation increases action potential duration dispersion and decreases ventricular fibrillation threshold via β1-adrenoceptor activation in the crystalloid perfused normal rabbit heart☆☆☆ 
International Journal of Cardiology  2014;172(1):144-154.
Background/objectives
Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility.
Methods
Experiments were conducted in isolated New Zealand white rabbit hearts (2.0–2.5 kg, n = 25). The effects of CCM (± 20 mA, 10 ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8 μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS.
Results
CCM significantly shortened MAPD close to the stimulation site (Basal: 102 ± 5 [CCM] vs. 131 ± 6 [Control] ms, P < 0.001). VFT was reduced during CCM (2.6 ± 0.6 [CCM] vs. 6.1 ± 0.8 [Control] mA, P < 0.01) and was correlated (r2 = 0.40, P < 0.01) with increased MAPD dispersion (26 ± 4 [CCM] vs. 5 ± 1 [Control] ms, P < 0.01) (n = 8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation.
Conclusions
CCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart.
doi:10.1016/j.ijcard.2013.12.184
PMCID: PMC3978661  PMID: 24456882
ACh, acetylcholine; APD, action potential duration; CCM, cardiac contractility modulation; LV, left ventricle; MAPD90, monophasic action potential duration at 90% repolarization; NE, norepinephrine; VFT, ventricular fibrillation threshold; Cardiac contractility modulation; Non-excitatory stimulation (NES); Ventricular arrhythmia; Ventricular fibrillation; Action potential duration dispersion
16.  Secondary amyloidosis in an alkaptonuric aortic valve☆ 
International Journal of Cardiology  2014;172(1):e121-e123.
doi:10.1016/j.ijcard.2013.12.117
PMCID: PMC3991337  PMID: 24456888
Ochronosis; Amyloidosis; Aortic valve; Stenosis; Calcification
17.  Use of drug treatment for secondary prevention of cardiovascular disease in urban and rural communities of China: China Kadoorie Biobank Study of 0.5 million people☆ 
Aims
Relatively little is known about the use of medication for the secondary prevention of cardiovascular disease (CVD) events in China, and the relevance to it of socioeconomic, lifestyle and health-related factors.
Methods and results
We analysed cross-sectional data from the China Kadoorie Biobank (CKB) of 512,891 adults aged 30–79 years recruited from 1737 rural and urban communities in China. Information about doctor-diagnosed ischaemic heart disease (IHD) and stroke, and the use of medication for the secondary prevention of CVD events, were recorded by interview. Multivariate logistic regression was used to estimate odds ratios (ORs) for use of secondary preventive treatment, adjusting simultaneously for age, sex, area and education. Overall, 23,129 (4.5%) participants reported a history of CVD (3.0% IHD, 1.7% stroke). Among them, 35% reported current use of any of 6 classes of drug (anti-platelet, statins, diuretics, ACE-I, β-blockers or calcium-channel blockers) for the prevention of CVD events, with the rate of usage greater in those with older age, higher levels of income, education, BMI or blood pressure. The use of these agents was associated positively with history of diagnosed hypertension (OR 7.5; 95% confidence intervals: 7.08–8.06) and diabetes (1.40; 1.28–1.52) and inversely with self-rated health status, but there was no association with years since diagnosis.
Conclusions
Despite recent improvements in hospital care in China, only one in three individuals with prior CVD was routinely treated with any proven secondary preventive drugs. The treatment rates were correlated with the existence of other risk factors, in particular evidence of hypertension.
doi:10.1016/j.ijcard.2013.12.065
PMCID: PMC3991854  PMID: 24461961
Ischemic heart disease; Stroke; Secondary prevention; Cardiovascular medication; Rural and urban communities; China
18.  Trajectories of the Framingham general cardiovascular risk profile in midlife and poor motor function later in life: The Whitehall II study☆☆☆ 
Background
Vascular risk factors are associated with increased risk of cognitive impairment and dementia, but their association with motor function, another key feature of aging, has received little research attention. We examined the association between trajectories of the Framingham general cardiovascular disease risk score (FRS) over midlife and motor function later in life.
Methods
A total of 5376 participants of the Whitehall II cohort study (29% women) who had up to four repeat measures of FRS between 1991–1993 (mean age = 48.6 years) and 2007–2009 (mean age = 65.4 years) and without history of stroke or coronary heart disease in 2007–2009 were included. Motor function was assessed in 2007–2009 through objective tests (walking speed, chair rises, balance, finger tapping, grip strength). We used age- and sex-adjusted linear mixed models.
Results
Participants with poorer performances for walking speed, chair rises, and balance in 2007–2009 had higher FRS concurrently and also in 1991–1993, on average 16 years earlier. These associations were robust to adjustment for cognition, socio-economic status, height, and BMI, and not explained by incident mobility limitation prior to motor assessment. No association was found with finger tapping and grip strength.
Conclusions
Cardiovascular risk early in midlife is associated with poor motor performances later in life. Vascular risk factors play an important and under-recognized role in motor function, independently of their impact on cognition, and suggest that better control of vascular risk factors in midlife may prevent physical impairment and disability in the elderly.
doi:10.1016/j.ijcard.2013.12.051
PMCID: PMC3991855  PMID: 24461963
CVD, cardiovascular disease; FRS, Framingham general cardiovascular disease risk score; SES, socioeconomic status; BMI, body mass index; SD, standard deviation; Cardiovascular risk score; Motor function; Aging; Stroke; Cohort study
19.  Reduced right ventricular ejection fraction and increased mortality in chronic systolic heart failure patients receiving beta-blockers: Insights from the BEST trial 
Background
Right ventricular ejection fraction (RVEF) <20% is an independent predictor of poor outcomes in patients with advanced chronic systolic heart failure (HF). The aim of this study was to examine if the adverse effect of abnormally reduced RVEF varies by the receipt of beta-blockers.
Methods
In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 patients with chronic advanced HF and left ventricular ejection fraction <35%, receiving standard background therapy with renin-angiotensin inhibition, digoxin, and diuretics, were randomized to receive bucindolol or placebo. Of these 2008 had data on baseline RVEF, and 14% (146/1017) and 13% (125/991) of the patients receiving bucindolol and placebo respectively had RVEF <20%.
Results
Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF ≥20% and <20% respectively (unadjusted hazard ratios {HR}, 1.33; 95% confidence intervals {CI}, 0.99–1.78; p =0.055 and adjusted HR, 0.99; 95% CI, 0.71–1.37; p =0.934). Among those receiving bucindolol, all-cause mortality occurred in 28% and 49% of patients with RVEF ≥20% and <20% respectively (unadjusted HR, 2.15; 95% CI, 1.65–2.80; p <0.001 and adjusted HR, 1.50; 95% CI, 1.08–2.07; p =0.016). These differences were statistically significant (unadjusted and adjusted p for interaction, 0.016 and 0.053 respectively).
Conclusions
In ambulatory patients with chronic advanced systolic HF receiving renin-angiotensin inhibition, digoxin, and diuretics, RVEF <20% had no intrinsic association with mortality. However, in those receiving additional therapy with bucindolol, RVEF <20% had a significant independent association with increased risk of mortality.
doi:10.1016/j.ijcard.2011.05.051
PMCID: PMC3395778  PMID: 21704392
Heart failure; Right ventricle; Bucindolol; Mortality; Morbidity
20.  Ventilatory efficiency slope correlates with functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension☆,☆☆,★ 
International journal of cardiology  2013;169(6):445-448.
Background
Cardiopulmonary exercise testing is widely used in a variety of cardiovascular conditions. Ventilatory efficiency slope can be derived from submaximal exercise testing. The present study sought to evaluate the relationship between ventilatory efficiency slope and functional capacity, outcomes, and disease severity in pediatric patients with pulmonary hypertension.
Methods
Seventy six children and young adults with a diagnosis of pulmonary hypertension (PH) performed 258 cardiopulmonary exercise tests from 2001 to 2011. Each individual PH test was matched to a control test. Ventilatory efficiency slope was compared to traditional measures of functional capacity and disease severity including WHO functional classification, peak oxygen consumption, and invasive measures of pulmonary arterial pressures and pulmonary vascular resistance.
Results
Ventilatory efficiency slope was significantly higher in patients with pulmonary arterial hypertension, with an estimated increase of 7.2 for each increase in WHO class (p < 0.0001), compared with normal control subjects (38.9 vs. 30.9, p<0.001). Ventilatory efficiency slope correlated strongly with invasive measures of disease severity including pulmonary vascular resistance index (r =0.61), pulmonary artery pressure (r =0.58), mean pulmonary artery pressure/mean aortic pressure ratio (r =0.52), and peak VO2 (r=−0.58). Ventilatory efficiency slope in 12 patients with poor outcomes (9 death, 3 lung transplant), was significantly elevated compared to patients who did not (51.1 vs. 37.9, p<0.001).
Conclusions
Ventilatory efficiency slope correlates well with invasive and noninvasive markers of disease severity including peak VO2, WHO functional class, and catheterization variables in pediatric patients with PH. Ventilatory efficiency slope may be a useful noninvasive marker for disease severity.
doi:10.1016/j.ijcard.2013.10.012
PMCID: PMC3909671  PMID: 24144928
Ventilatory efficiency slope; VE/VCO2 slope; Pulmonary hypertension; Cardiopulmonary exercise testing; Pediatric
21.  Cardiac resynchronization therapy and AV optimization increase myocardial oxygen consumption, but increase cardiac function more than proportionally☆ 
International Journal of Cardiology  2014;171(2):144-152.
Background
The mechanoenergetic effects of atrioventricular delay optimization during biventricular pacing (“cardiac resynchronization therapy”, CRT) are unknown.
Methods
Eleven patients with heart failure and left bundle branch block (LBBB) underwent invasive measurements of left ventricular (LV) developed pressure, aortic flow velocity-time-integral (VTI) and myocardial oxygen consumption (MVO2) at 4 pacing states: biventricular pacing (with VV 0 ms) at AVD 40 ms (AV-40), AVD 120 ms (AV-120, a common nominal AV delay), at their pre-identified individualised haemodynamic optimum (AV-Opt); and intrinsic conduction (LBBB).
Results
AV-120, relative to LBBB, increased LV developed pressure by a mean of 11(SEM 2)%, p = 0.001, and aortic VTI by 11(SEM 3)%, p = 0.002, but also increased MVO2 by 11(SEM 5)%, p = 0.04.
AV-Opt further increased LV developed pressure by a mean of 2(SEM 1)%, p = 0.035 and aortic VTI by 4(SEM 1)%, p = 0.017. MVO2 trended further up by 7(SEM 5)%, p = 0.22.
Mechanoenergetics at AV-40 were no different from LBBB.
The 4 states lay on a straight line for Δexternal work (ΔLV developed pressure × Δaortic VTI) against ΔMVO2, with slope 1.80, significantly > 1 (p = 0.02).
Conclusions
Biventricular pacing and atrioventricular delay optimization increased external cardiac work done but also myocardial oxygen consumption. Nevertheless, the increase in cardiac work was ~ 80% greater than the increase in oxygen consumption, signifying an improvement in cardiac mechanoenergetics. Finally, the incremental effect of optimization on external work was approximately one-third beyond that of nominal AV pacing, along the same favourable efficiency trajectory, suggesting that AV delay dominates the biventricular pacing effect — which may therefore not be mainly “resynchronization”.
doi:10.1016/j.ijcard.2013.10.026
PMCID: PMC3919205  PMID: 24332598
Biventricular pacing; Optimization; Myocardial oxygen consumption
22.  Ethnic differences in Ankle Brachial Index are Present in Middle-Aged Individuals without Peripheral Arterial Disease 
International journal of cardiology  2011;162(3):228-233.
Introduction
To better understand the basis for previously reported ethnic differences in ankle brachial index (ABI), we investigated whether these differences were present in individuals without known peripheral arterial disease (PAD).
Methods
We used data from National Health and Nutrition Examination surveys (NHANES 1999–2004) to determine whether ethnic differences were present in respondents without PAD (1≤ABI≤1.3). We assessed whether ethnicity was an independent predictor of ABI and ankle systolic blood pressure (SBP) in linear regression models that adjusted for conventional and novel cardiovascular risk factors. To minimize effects of atherosclerosis on ABI, we studied adults aged ≤ 60 years, and also repeated our analyses in a subset aged ≤ 50 years that did not have risk factors for PAD.
Results
3348 participants aged ≤ 60 years were included in the study. Mean ABI was 1.11 in non-Hispanic Blacks (NHB) and 1.13 in non-Hispanic Whites (NHW) (P <0.0001). In multivariable linear regression analysis that adjusted for age, gender, ethnicity, smoking, height, diabetes, brachial SBP, dyslipidemia, diabetes, renal function, concurrent cardiovascular disease, and plasma levels of homocysteine, fibrinogen and C-reactive protein, NHB had lower ABI than NHW (β= − 0.03± 0.004, P < 0.00001). Although, NHBs had higher ankle SBP than NHWs (by 5.3 mm Hg), NHBs had a lower mean ankle SBP (β= − 3.663 mm Hg ± 0.500, P <.0001) after adjusting for clinical covariates, including brachial SBP, in multivariable analysis.
Conclusion
Ethnic differences in ABI are present in middle-aged adults at low risk for peripheral atherosclerosis.
doi:10.1016/j.ijcard.2011.05.068
PMCID: PMC3174274  PMID: 21652099
ankle brachial index; ethnicity
23.  The obesity paradox in men with coronary heart disease and heart failure: The role of muscle mass and leptin☆☆☆★ 
Aims
We have investigated the role of muscle mass, natriuretic peptides and adipokines in explaining the obesity paradox.
Background
The obesity paradox relates to the association between obesity and increased survival in patients with coronary heart disease (CHD) or heart failure (HF).
Methods
Prospective study of 4046 men aged 60–79 years followed up for a mean period of 11 years, during which 1340 deaths occurred. The men were divided according to the presence of doctor diagnosed CHD and HF: (i) no CHD or HF ii), with CHD (no HF) and (iii) with HF.
Results
Overweight (BMI 25–9.9 kg/m2) and obesity (BMI ≥ 30 kg/m2) were associated with lower mortality risk compared to men with normal weight (BMI 18.5–24.9 kg/m2) in those with CHD [hazards ratio (HR) 0.71 (0.56,0.91) and 0.77 (0.57,1.04); p = 0.04 for trend] and in those with HF [HR 0.57 (0.28,1.16) and 0.41 (0.16,1.09; p = 0.04 for trend). Adjustment for muscle mass and NT-proBNP attenuated the inverse association in those with CHD (no HF) [HR 0.78 (0.61,1.01) and 0.96 (0.68,1.36) p = 0.60 for trend) but made minor differences to those with HF [p = 0.05]. Leptin related positively to mortality in men without HF but inversely to mortality in those with HF; adjustment for leptin abolished the BMI mortality association in men with HF [HR 0.82 (0.31,2.20) and 0.99 (0.27,3.71); p = 0.98 for trend].
Conclusion
The lower mortality risk associated with excess weight in men with CHD without HF may be due to higher muscle mass. In men with HF, leptin (possibly reflecting cachexia) explain the inverse association.
doi:10.1016/j.ijcard.2013.11.043
PMCID: PMC3909461  PMID: 24331120
NT-proBNP, N-terminal pro-brain natriuretic peptide; HF, Heart failure; MI, Myocardial infarction; CHD, Coronary heart disease; CRP, C-reactive protein; WC, Waist circumference; BMI, Body mass index; MAMC, Mid arm muscle circumference; Obesity; Mortality; Cardiovascular disease; Leptin; Heart failure
24.  The adenosine A2A receptor — Myocardial protectant and coronary target in endotoxemia 
International journal of cardiology  2011;166(3):10.1016/j.ijcard.2011.11.075.
Background
Cardiac injury and dysfunction are contributors to disease progression and mortality in sepsis. This study evaluated the cardiovascular role of intrinsic A2A adenosine receptor (A2AAR) activity during lipopolysaccharide (LPS)-induced inflammation.
Methods
We assessed the impact of 24 h of LPS challenge (20 mg/kg, IP) on cardiac injury, coronary function and inflammatory mediator levels in Wild-Type (WT) mice and mice lacking functional A2AARs (A2AAR KO).
Results
Cardiac injury was evident in LPS-treated WTs, with ∼7-fold elevation in serum cardiac troponin I (cTnI), and significant ventricular and coronary dysfunction. Absence of A2AARs increased LPS-provoked cTnI release at 24 h by 3-fold without additional demise of contraction function. Importantly, A2AAR deletion per se emulated detrimental effects of LPS on coronary function, and LPS was without effect in coronary vessels lacking A2AARs. Effects of A2AAR KO were independent of major shifts in circulating C-reactive protein (CRP) and haptoglobin. Cytokine responses were largely insensitive to A2AAR deletion; substantial LPS-induced elevations (up to 100-fold) in IFN-γ and IL-10 were unaltered in A2AAR KO mice, as were levels of IL-4 and TNF-α. However, late elevations in IL-2 and IL-5 were differentially modulated by A2AAR KO (IL-2 reduced, IL-5 increased). Data demonstrate that in the context of LPS-triggered cardiac and coronary injury, A2AAR activity protects myocardial viability without modifying contractile dysfunction, and selectively modulates cytokine (IL-2, IL-5) release. A2AARs also appear to be targeted by LPS in the coronary vasculature.
Conclusions
These experimental data suggest that preservation of A2AAR functionality might provide therapeutic benefit in human sepsis.
doi:10.1016/j.ijcard.2011.11.075
PMCID: PMC3875340  PMID: 22192288
Adenosine receptors; Cardiac dysfunction; Cytokines; Inflammation; Troponin
25.  Baseline Characteristics, Quality of Care, and Outcomes of Younger and Older Medicare Beneficiaries Hospitalized with Heart Failure: Findings from the Alabama Heart Failure Project 
Background
Most studies of heart failure (HF) in Medicare beneficiaries have excluded patients age <65 years. We examined baseline characteristics, quality of care, and outcomes among younger and older Medicare beneficiaries hospitalized with HF in the Alabama Heart Failure Project.
Methods
Of the 8049 Medicare beneficiaries discharged alive with a primary discharge diagnosis of HF in 1998–2001 from 106 Alabama hospitals, 991 (12%) were younger (age <65 years). After excluding 171 patients discharge to hospice care, 7867 patients were considered eligible for left ventricular systolic function (LVSF) evaluation and 2211 patients with left ventricular ejection fraction <45% and without contraindications were eligible for angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy.
Results
Nearly half of the younger HF patients (45% versus 22% for ≥65 years; p<0.001) were African American. LVSF was evaluated in 72%, 72%, 70% and 60% (overall p<0.001) and discharge prescriptions of ACE inhibitors or ARBs were given to 83%, 77%, 75% and 75% of eligible patients (overall p=0.013) among those <65, 65–74, 75–84 and ≥85 years, respectively. During 9 years of follow-up, all-cause mortality occurred in 54%, 61%, 71% and 80% (overall p<0.001) and hospital readmission due to worsening HF occurred in 65%, 60%, 55% and 48% (overall p<0.001) of those <65, 65–74, 75–84 and ≥85 years, respectively.
Conclusion
Medicare beneficiaries <65 years with HF, nearly half of whom were African American, generally received better quality of care, had lower mortality, but had higher re-hospitalizations due to HF.
doi:10.1016/j.ijcard.2011.05.003
PMCID: PMC3395759  PMID: 21621285
heart failure; age; Medicare; quality of care; outcomes

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