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4.  Chronic Hypoxemia in Late Gestation Decreases Cardiomyocyte Number but Does Not Change Expression of Hypoxia‐Responsive Genes 
Placental insufficiency is the leading cause of intrauterine growth restriction in the developed world and results in chronic hypoxemia in the fetus. Oxygen is essential for fetal heart development, but a hypoxemic environment in utero can permanently alter development of cardiomyocytes. The present study aimed to investigate the effect of placental restriction and chronic hypoxemia on total number of cardiomyocytes, cardiomyocyte apoptosis, total length of coronary capillaries, and expression of genes regulated by hypoxia.
Methods and Results
We induced experimental placental restriction from conception, which resulted in fetal growth restriction and chronic hypoxemia. Fetal hearts in the placental restriction group had fewer cardiomyocytes, but interestingly, there was no difference in the percentage of apoptotic cardiomyocytes; the abundance of the transcription factor that mediates hypoxia‐induced apoptosis, p53; or expression of apoptotic genes Bax and Bcl2. Likewise, there was no difference in the abundance of autophagy regulator beclin 1 or expression of autophagic genes BECN1, BNIP3, LAMP1, and MAP1LC3B. Furthermore, fetuses exposed to normoxemia (control) or chronic hypoxemia (placental restriction) had similar mRNA expression of a suite of hypoxia‐inducible factor target genes, which are essential for angiogenesis (VEGF, Flt1, Ang1, Ang2, and Tie2), vasodilation (iNOS and Adm), and glycolysis (GLUT1 and GLUT3). In addition, there was no change in the expression of PKC‐ε, a cardioprotective gene with transcription regulated by hypoxia in a manner independent of hypoxia‐inducible factors. There was an increased capillary length density but no difference in the total length of capillaries in the hearts of the chronically hypoxemic fetuses.
The lack of upregulation of hypoxia target genes in response to chronic hypoxemia in the fetal heart in late gestation may be due to a decrease in the number of cardiomyocytes (decreased oxygen demand) and the maintenance of the total length of capillaries. Consequently, these adaptive responses in the fetal heart may maintain a normal oxygen tension within the cardiomyocyte of the chronically hypoxemic fetus in late gestation.
PMCID: PMC4310356  PMID: 25085511
angiogenesis; apoptosis; hypoxia; myocytes; pregnancy
5.  Implantable Defibrillators for Secondary Prevention of Sudden Cardiac Death in Cardiac Surgery Patients With Perioperative Ventricular Arrhythmias 
Randomized studies of implantable cardioverter defibrillators (ICD) have excluded sudden cardiac death survivors who had revascularization before or after an arrhythmic event. To evaluate the role of ICD and the effects of clinical variables including degree of revascularization, we studied cardiac surgery patients who had an ICD implanted for sustained perioperative ventricular arrhythmias.
Methods and Results
The electronic database for Southern California Kaiser Foundation hospitals was searched for patients who had cardiac surgery between 1999 and 2005 and an ICD implanted within 3 months of surgery. One hundred sixty‐four patients were identified; 93/164 had an ICD for sustained pre‐ or postoperative ventricular tachycardia or fibrillation requiring resuscitation. Records were reviewed for the following: presenting arrhythmia, ejection fraction, and degree of revascularization. The primary end point was total mortality (TM) and/or appropriate ICD therapy (ICD‐T), and secondary end points are TM and ICD‐T. During the mean follow up of 49 months, the primary endpoint of TM+ICD‐T and individual end points of TM and ICD‐T were observed in 52 (56%), 35 (38%), and 28 (30%) patients, respectively, with 55% of TM, and 23% of ICD‐T occurring within 2 years of implant. In multivariate risk analysis, none of the following was associated with any of the end points: incomplete revascularization, presenting ventricular arrhythmia, and timing of arrhythmias.
Our data supports the recent guidelines for ICD in this cohort of patients, as the presence of irreversible substrate and triggers of ventricular arrhythmias, cannot be reliably excluded even with complete revascularization. Further studies are needed to understand this complex group of patients.
PMCID: PMC4310357  PMID: 25146702
implantable defibrillator; perioperative ventricular arrhythmias; revascularization
6.  Tumor Necrosis Factor‐Like Weak Inducer of Apoptosis or Fn14 Deficiency Reduce Elastase Perfusion‐Induced Aortic Abdominal Aneurysm in Mice 
Abdominal aortic aneurysm (AAA) involves leukocyte recruitment, inflammatory cytokine production, vascular cell apoptosis, neovascularization, and vascular remodeling, all of which contribute to aortic dilatation. Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) is a cytokine implicated in proinflammatory responses, angiogenesis, and matrix degradation but its role in AAA formation is currently unknown.
Methods and Results
Experimental AAA with aortic elastase perfusion in mice was induced in wild‐type (WT), TWEAK deficient (TWEAK KO), or Fn14‐deficient (Fn14 KO) mice. TWEAK or Fn14 KO deficiency reduced aortic expansion, lesion macrophages, CD3+ T cells, neutrophils, CD31+ microvessels, CCL2 and CCL5 chemokines expression, and MMP activity after 14 days postperfusion. TWEAK and Fn14 KO mice also showed a reduced loss of medial vascular smooth muscle cells (VSMC) that was related to a reduced number of apoptotic cells in these animals compared with WT mice. Aortas from WT animals present a higher disruption of the elastic layer and MMP activity than those from TWEAK or Fn14 KO mice, indicating a diminished vascular remodeling in KO animals. In vitro experiments unveiled that TWEAK induces CCL5 secretion and MMP‐9 activation in both VSMC and bone marrow‐derived macrophages, and decrease VSMC viability, effects dependent on Fn14.
TWEAK/Fn14 axis participates in AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, matrix‐degrading protease expression, and vascular remodeling. Blocking TWEAK/Fn14 interaction could be a new target for the treatment of AAA.
PMCID: PMC4310358  PMID: 25092786
aneurysm; Fn14; inflammation; MMP activity; TWEAK
7.  Pulmonary Hypertension in Mitral Regurgitation 
PMCID: PMC4310359  PMID: 25103202
mitral regurgitation; mitral valve regurgitation; pulmonary hypertension
8.  Socioeconomic Position and Incidence of Ischemic Stroke in Denmark 2003–2012. A Nationwide Hospital‐Based Study 
A greater burden of stroke risk factors in general is associated with a higher risk for stroke among people of lower than those of higher socioeconomic position. The relative impact of individual stroke risk factors is still unclear.
Methods and Results
We studied the relations between socioeconomic position, measured as household income and length of education, and all hospital admissions for a first ischemic stroke among 54 048 people over the age of 40 years in Denmark in 2003–2012 in comparison with the general Danish population (23.5 million person‐years). We also studied the cardiovascular risk factor profile associated with socioeconomic position in stroke patients. Relative risks for stroke were estimated in log‐linear Poisson regression models. The risk for hospitalization for a first ischemic stroke was almost doubled for people in the lowest income group, and the risk of those of working age (<65 years) was increased by 36% among people with the shortest education. Diabetes, obesity, smoking, and high alcohol consumption in particular and, to a lesser extent, previous myocardial infarction or intermittent arterial claudication were significantly overrepresented among stroke patients with lower socioeconomic position. Atrial fibrillation and hypertension were not.
In Denmark, there is a strong relation between low socioeconomic position and risk for hospitalization for stroke. Lifestyle, as indicated by smoking, obesity, and alcohol consumption, and diabetes appears to increase the risk for stroke in people with lower socioeconomic position.
PMCID: PMC4310360  PMID: 25030354
disposable income; education; ischemic stroke; socioeconomic position
9.  Aspirin Use and Risk of Atrial Fibrillation in the Physicians' Health Study 
Inflammatory processes have been associated with an increased risk of atrial fibrillation (AF), potentially allowing for preventive therapy by anti‐inflammatory agents such as aspirin. However, the effect of chronic aspirin on the incidence of AF has not been evaluated in a prospective cohort followed for an extended period.
Methods and Results
This study was comprised of a prospective cohort of 23 480 male participants of the Physicians' Health Study. Aspirin intake and covariates were estimated using self‐reported questionnaires. Incident AF was ascertained through yearly follow‐up questionnaires. Cox's regression, with adjustment for multiple covariates, was used to estimate relative risk of AF. Average age at baseline was 65.1±8.9 years. During a mean follow‐up of 10.0 years, 2820 cases of AF were reported. Age‐standardized incidence rates were 12.6, 11.1, 12.7, 11.3, 15.8, and 13.8/1000 person‐years for people reporting baseline aspirin intake of 0, <14 days per year, 14 to 30 days per year, 30 to 120 days per year, 121 to 180 days per year, and >180 days per year, respectively. Multivariable adjusted hazard ratios (95% confidence interval) for incident AF were 1.00 (reference), 0.88 (0.76 to 1.02), 0.93 (0.76 to 1.14), 0.96 (0.80 to 1.14), 1.07 (0.80 to 1.14), and 1.04 (0.94 to 1.15) across consecutive categories of aspirin intake. Analysis of the data using time‐varying Cox's regression model to update aspirin intake over time showed similar results.
In a large cohort of males followed for a long period, we did not find any association between aspirin use and incident AF.
PMCID: PMC4310361  PMID: 24980132
aspirin; atrial fibrillation; epidemiology; risk factors
10.  Plasma Phospholipid Fatty Acid Biomarkers of Dietary Fat Quality and Endogenous Metabolism Predict Coronary Heart Disease Risk: A Nested Case‐Control Study Within the Women's Health Initiative Observational Study 
Although the relationship between dietary fat quality and coronary heart disease (CHD) risk has been evaluated, typically using diet questionnaires, results are inconsistent and data in postmenopausal women are limited. Plasma phospholipid fatty acid (PL‐FA) profiles, reflecting dietary intake and endogenous FA metabolism, may better predict diet–CHD risk.
Methods and Results
Using a nested case‐control design, we assessed the association between plasma PL‐FA profiles and CHD risk in 2448 postmenopausal women (1224 cases with confirmed CHD and 1224 controls matched for age, enrollment date, race/ethnicity, and absence of CHD at baseline and after 4.5 years of follow‐up) participating in the Women's Health Initiative observational study. PL‐FA profile was measured using gas chromatography. Product/precursor ratios were used to estimate stearoyl‐CoA‐desaturase (16:1n‐7/16:0, 18:1n‐9/18:0), Δ6‐desaturase (20:3n‐6/18:2n‐6), and Δ5‐desaturase (20:4n‐6/20:3n‐6) activities, indicators of endogenous FA metabolism. Multivariate conditional logistic regression was used to obtain odds ratios (95% CIs) for CHD risk. While no associations were observed for the predominant PL fatty acid (16:0, 18:0, 18:1n‐9, and 18:2n‐6), plasma PL–saturated fatty acid (1.20 [1.08 to 1.32]) and endogenously synthesized PL ω6 fatty acids (20:3n‐6; 3.22 [1.95 to 5.32]), 22:5n‐6; 1.63 [1.20 to 2.23]) and Δ6‐desaturase (1.25 [1.11 to 1.41]) were positively associated with CHD risk. PL‐ω3 fatty acids (20:5n‐3; 0.73 [0.58 to 0.93], 22:5n‐3; 0.56 [0.33 to 0.94], 22:6n‐3; 0.56 [0.39 to 0.80]), 18:1n‐7 (0.54 [0.29 to 0.99]), and Δ5‐desaturase (0.78 [0.70 to 0.88]) were inversely associated with CHD risk. Results support current guidelines regarding regular fish consumption. Additional findings include associations between endogenously synthesized fatty acids and CHD risk, which were partly explained by changes in Δ6‐desaturase and Δ5‐desaturase indexes, suggesting that in vivo metabolism may also play an important role in predicting CHD risk in this cohort of postmenopausal women.
Clinical Trial Registration
URL:, Unique identifier: NCT01864122.
PMCID: PMC4310362  PMID: 25122663
diet; fatty acids; risk factors; women
11.  Galectin‐3, a Biomarker Linking Oxidative Stress and Inflammation With the Clinical Outcomes of Patients With Atherothrombosis 
Galectin‐3 (Gal‐3) participates in different mechanisms involved in atherothrombosis, such as inflammation, proliferation, or macrophage chemotaxis. Thus, there have been committed intensive efforts to elucidate the function of Gal‐3 in cardiovascular (CV) diseases. The role of Gal‐3 as a circulating biomarker has been demonstrated in patients with heart failure, but its importance as a biomarker in atherothrombosis is still unknown.
Methods and Results
Because Gal‐3 is involved in monocyte‐to‐macrophage transition, we used fresh isolated monocytes and the in vitro model of macrophage differentiation of THP‐1 cells stimulated with phorbol myristate acetate (PMA). Gal‐3 release is increased by PMA in human monocytes and macrophages, a process involving exosomes and regulated by reactive oxygen species/NADPH oxidase activity. In asymptomatic subjects (n=199), Gal‐3 plasma levels are correlated with NADPH oxidase activity in peripheral blood mononuclear cells (r=0.476; P<0.001) and carotid intima‐media thickness (r=0.438; P<0.001), a surrogate marker of atherosclerosis. Accordingly, Gal‐3 plasma concentrations are increased in patients with carotid atherosclerosis (n=158), compared to control subjects (n=115; 14.3 [10.7 to 16.9] vs. 10.4 [8.6 to 12.5] ng/mL; P<0.001). Finally, on a 5‐year follow‐up study in patients with peripheral artery disease, Gal‐3 concentrations are significantly and independently associated with an increased risk for CV mortality (hazard ratio=2.24, 95% confidence interval: 1.06 to 4.73, P<0.05).
Gal‐3 extracellular levels could reflect key underlying mechanisms involved in atherosclerosis etiology, development, and plaque rupture, such as inflammation, infiltration of circulating cells and oxidative stress. Moreover, circulating Gal‐3 concentrations are associated with clinical outcomes in patients with atherothrombosis.
PMCID: PMC4310363  PMID: 25095870
atherothrombosis; biomarkers; inflammation; mortality; oxidative stress
12.  Association of Fat Density With Subclinical Atherosclerosis 
Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis.
Methods and Results
Participants were drawn from the Multi‐Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable‐adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age‐/sex‐specific cutoffs). Per 5‐unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC.
Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis.
PMCID: PMC4310364  PMID: 25169793
atherosclerosis; epidemiology; fat density; obesity
13.  β2‐Microglobulin, Cystatin C, and Creatinine and Risk of Symptomatic Peripheral Artery Disease 
β2‐Microglobulin and cystatin C may have advantages over creatinine in assessing risk associated with kidney function. We therefore investigated whether emerging filtration markers, β2‐microglobulin and cystatin C, are prospectively associated with risk of the development of peripheral artery disease (PAD).
Methods and Results
We conducted nested case‐control studies among women within the Nurses’ Health Study (1990–2010) and among men within the Health Professionals Follow‐up Study (1994–2008) with the use of archived blood samples collected before PAD diagnosis. During follow‐up, symptomatic PAD was confirmed in 144 women and 143 men. Controls were matched 3:1 based on age, race, smoking status, fasting status, and date of blood sampling. Conditional logistic regression models were used to estimate relative risks (RRs) and were adjusted for plasma creatinine and cardiovascular risk factors. In women, the RRs (95% CI) per 1‐SD) increment were 1.16 (0.85 to 1.58) for β2‐microglobulin and 0.94 (0.69 to 1.28) for cystatin C. Corresponding RRs in men were 1.50 (1.08 to 2.09) for β2‐microglobulin and 1.54 (1.07 to 2.22) for cystatin C. There was no association between creatinine and PAD risk in women, whereas the association in men (RR 1.41, 95% CI 1.10 to 1.81) disappeared after adjustment for either β2‐microglobulin or cystatin C. In pooled analyses of men and women, only β2‐microglobulin was associated with PAD risk (RR 1.31, 95% CI 1.04 to 1.64).
In pooled analyses, β2‐microglobulin was associated with an increased risk of symptomatic PAD; a similar association with cystatin C was observed only in men. The findings suggest that β2‐microglobulin may capture the atherosclerosis‐promoting or atherosclerosis‐related elements of kidney dysfunction better than creatinine.
PMCID: PMC4310365  PMID: 24980133
creatinine; cystatin C; kidney; peripheral artery disease; β2‐microglobulin
14.  Venous Thromboembolism and Varicose Veins Share Familial Susceptibility: A Nationwide Family Study in Sweden 
Varicose veins (VVs) have been associated with venous thromboembolism (VTE), but whether these diseases share familial susceptibility has not been determined. This nationwide study aimed to determine whether VTE shares familial susceptibility with VVs.
Methods and Results
Swedish Multigeneration Register data for persons aged 0 to 76 years during the period 1964–2008 were linked to the Swedish Inpatient and Outpatient Registers. Familial risks (standardized incidence ratios [SIRs]) of VTE and VVs were examined in 2 ways (ie, bidirectionally): risk of VTE in subjects whose siblings had been diagnosed with VVs and risk of VVs in persons whose siblings had been diagnosed with VTE. The analyses were repeated for spouses to determine the importance of shared adult family environment. In total, 96 810 siblings had VVs and 87 564 had VTE. An increased risk of VTE was observed in persons whose siblings had VVs (SIR 1.30, 95% CI 1.26 to 1.33), whereas persons whose siblings had VTE had an increased risk of VVs (SIR 1.30, 95% CI 1.27 to 1.34). If 2 or more siblings were affected by VTE, the risk for VVs was 1.70 (95% CI 1.53 to 1.88). Conversely, if 2 or more siblings were affected by VVs, the risk for VTE was 1.52 (95% CI 1.38 to 1.67). In spouses of VTE patients, a minor increased risk of VVs was observed (SIR 1.05 for husbands, SIR 1.06 for wives). The risk of VTE in spouses of VV patients was similarly small (SIR 1.01 for husbands, SIR 1.05 for wives).
VVs and VTE share familial susceptibility. This novel finding suggests the existence of shared familial and possibly genetic factors.
PMCID: PMC4310366  PMID: 25158864
embolism; epidemiology; genetics; thrombosis; veins
15.  Pistachio Nut Consumption Modifies Systemic Hemodynamics, Increases Heart Rate Variability, and Reduces Ambulatory Blood Pressure in Well‐Controlled Type 2 Diabetes: a Randomized Trial 
Managing cardiovascular risk factors is important for reducing vascular complications in type 2 diabetes, even in individuals who have achieved glycemic control. Nut consumption is associated with reduced cardiovascular risk; however, there is mixed evidence about the effect of nuts on blood pressure (BP), and limited research on the underlying hemodynamics. This study assessed the effect of pistachio consumption on BP, systemic hemodynamics, and heart rate variability in adults with well‐controlled type 2 diabetes.
Methods and Results
We enrolled 30 adults (40 to 74 years) with type 2 diabetes in a randomized, crossover, controlled feeding study. After a 2‐week run‐in period, participants consumed a low‐fat control diet (27% fat) containing low‐fat/high‐carbohydrate snacks and a moderate‐fat diet (33% fat) containing pistachios (20% of total energy) for 4 weeks each, separated by a 2‐week washout. Following each diet period, we assessed BP, systemic hemodynamics, and heart rate variability at rest and during acute mental stress, and, in a subset of participants (n=21), 24‐hour ambulatory BP. BP at rest and during stress did not differ between treatments. The pistachio diet significantly reduced total peripheral resistance (−3.7±2.9%, P=0.004), increased cardiac output (3.1±2.3%, P=0.002), and improved some measures of heart rate variability (all P<0.05). Systolic ambulatory BP was significantly reduced by 3.5±2.2 mm Hg (P=0.046) following the pistachio diet, with the greatest reduction observed during sleep (−5.7±2.6 mm Hg, P=0.052).
A moderate‐fat diet containing pistachios modestly improves some cardiovascular risk factors in adults with well‐controlled type 2 diabetes.
Clinical Trial Registration
URL: Unique identifier: NCT00956735.
PMCID: PMC4310367  PMID: 24980134
blood pressure; heart rate variability; hemodynamics; nutrition; type 2 diabetes mellitus
16.  Improvement in Quality of Life After Catheter Ablation for Paroxysmal Versus Long‐standing Persistent Atrial Fibrillation: A Prospective Study With 3‐Year Follow‐up 
Changes in quality of life (QoL) after catheter ablation for long‐standing persistent atrial fibrillation (LSPAF) are not well described. We sought to compare QoL improvement after catheter ablation of paroxysmal atrial fibrillation (PAF) versus that after LSPAF.
Methods and Results
A total of 261 PAF and 126 LSPAF ablation recipients were prospectively followed for arrhythmia recurrence, QoL, hospital stay, and sick leave. In PAF versus LSPAF groups, 1.3±0.6 versus 1.6±0.7 procedures were performed per patient (P<0.00001) during a 3‐year follow‐up. Good arrhythmia control was achieved in 86% versus 87% of patients (P=0.69) and in 69% versus 69% of patients not receiving antiarrhythmic drugs (P=0.99). The baseline QoL was better in the PAF than in the LSPAF group (European Quality of Life Group instrument self‐report questionnaire visual analog scale: 66.4±14.2 versus 61.0±14.2, P=0.0005; European Quality of Life Group 3‐level, 5‐dimensional descriptive system: 71.4±9.2 versus 67.7±13.8, P=0.002). Postablation 3‐year increase in QoL was significant in both groups (all P<0.00001) and significantly lower in PAF versus LSPAF patients (visual analog scale: +5.0±14.5 versus +10.2±12.8, P=0.001; descriptive system: +5.9±14.3 versus +9.3±13.9, P=0.03). In multivariate analysis, LSPAF, less advanced age, shorter history of AF and good arrhythmia control were consistently associated with postablation 3‐year improvement in QoL. Days of hospital stay for cardiovascular reasons and days on sick leave per patient/year were significantly reduced in both groups.
Patients with LSPAF had worse baseline QoL. The magnitude of QoL improvement after ablation of LSPAF was significantly greater compared with after ablation of PAF, particularly when good arrhythmia control was achieved without the use of antiarrhythmic drugs.
PMCID: PMC4310368  PMID: 25037195
atrial fibrillation; long‐standing persistent; paroxysmal; quality of life
17.  Practice Patterns and Trends in the Use of Medical Therapy in Patients Undergoing Percutaneous Coronary Intervention in Ontario 
Clinical guidelines emphasize medical therapy as the initial approach to the management of patients with stable coronary artery disease (CAD). However, the extent to which medical therapy is applied before and after percutaneous coronary intervention (PCI) in contemporary clinical practice is uncertain. We evaluated medication use for patients with stable CAD undergoing PCI, and assessed whether the COURAGE study altered medication use in the Canadian healthcare system.
Methods and Results
A population‐based cohort of 23 680 older patients >65 years old) with stable CAD undergoing PCI in Ontario between 2003 and 2010 was assembled. Optimal medical therapy (OMT) was defined as prescription for a β‐blocker, statin, and either angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker in the 90 days before PCI, and the same medications plus thienopyridine 90 days following PCI. Prior to PCI, 8023 (33.9%) patients were receiving OMT, 11 891 (50.2%) were on suboptimal therapy, and 3766 (15.9%) were not prescribed any medications of interest. There was significant improvement in medical therapy following PCI (OMT: 11 149 [47.1%], suboptimal therapy: 11 591 [48.9%], and none: 940 [4.0%], P<0.001). Utilization rate of OMT reduced significantly after the publication of COURAGE (34.9% before versus 32.8% after, P<0.001). Similarly, the rate of OMT following PCI was lower in the period after publication of COURAGE (47.3% before versus 46.9% after, P<0.001).
OMT was prescribed in about 1 in 3 patients prior to PCI and less than half after PCI. In contrast to the anticipated impact of COURAGE, we found lower rates of medication use in PCI patients after its publication.
PMCID: PMC4310369  PMID: 25122664
optimal medical therapy; outcomes; percutaneous coronary intervention; stable coronary artery disease
18.  Antifailure Therapy Including Spironolactone Improves Left Ventricular Energy Supply‐Demand Relations in Nonischemic Dilated Cardiomyopathy 
Left ventricular (LV) energy supply‐demand imbalance is postulated to cause “energy starvation” and contribute to heart failure (HF) in nonischemic dilated cardiomyopathy (NIDCM). Using cardiac magnetic resonance (CMR) and [11C] acetate positron emission tomography (PET), we evaluated LV perfusion and oxidative metabolism in NIDCM and the effects of spironolactone on LV supply‐demand relations.
Methods and Results
Twelve patients with NIDCM underwent CMR and PET at baseline and after ≥6 months of spironolactone therapy added to a standard HF regimen. The myocardial perfusion reserve index (MPRI) was calculated after gadolinium injection during adenosine, as compared to rest. The monoexponential clearance rate of [11C] acetate (kmono) was used to calculate the work metabolic index (WMI), an index of LV mechanical efficiency, and kmono/RPP (rate‐pressure product), an index of energy supply/demand. At baseline, the subendocardium was hypoperfused versus the subepicardium (median MPRI, 1.63 vs. 1.80; P<0.001), but improved to 1.80 (P<0.001) after spironolactone. The WMI increased (P=0.001), as did kmono/RPP (P=0.003). These improvements were associated with reverse remodeling, increased LV ejection fraction, and decreases in LV mass and systolic wall stress (all P<0.002).
NIDCM is associated with subendocardial hypoperfusion and impaired myocardial oxidative metabolism, consistent with energy starvation. Antifailure therapy improves parameters of energy starvation and is associated with augmented LV performance.
Clinical Trial Registration
URL: Unique identifier: ID NCT00574119.
PMCID: PMC4310370  PMID: 25164945
Energy metabolism; heart failure; magnetic resonance imaging; myocardial perfusion imaging; positron emission tomography
19.  Transgenic Knockdown of Cardiac Sodium/Glucose Cotransporter 1 (SGLT1) Attenuates PRKAG2 Cardiomyopathy, Whereas Transgenic Overexpression of Cardiac SGLT1 Causes Pathologic Hypertrophy and Dysfunction in Mice 
The expression of a novel cardiac glucose transporter, SGLT1, is increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG2. We sought to determine the role of SGLT1 in the pathogenesis of PRKAG2 cardiomyopathy and its role in cardiac structure and function.
Methods and Results
Transgenic mice with cardiomyocyte‐specific overexpression of human T400N mutant PRKAG2 cDNA (TGT400N) and transgenic mice with cardiomyocyte‐specific RNA interference knockdown of SGLT1 (TGSGLT1‐DOWN) were crossed to produce double‐transgenic mice (TGT400N/TGSGLT1‐DOWN). Tet‐off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were also constructed (TGSGLT‐ON). Relative to TGT400N mice, TGT400N/TGSGLT1‐DOWN mice exhibited decreases in cardiac SGLT1 expression (63% decrease, P<0.05), heart/body weight ratio, markers of cardiac hypertrophy, and cardiac glycogen content. TGT400N/TGSGLT1‐DOWN mice had less left ventricular dilation at age 12 weeks compared to TGT400N mice. Relative to wildtype (WT) mice, TGSGLT1‐ON mice exhibited increases in heart/body weight ratio, glycogen content, and markers of cardiac hypertrophy at ages 10 and 20 weeks. TGSGLT1‐ON mice had increased myocyte size and interstitial fibrosis, and progressive left ventricular dysfunction. When SGLT1 was suppressed after 10 weeks of overexpression (TGSGLT1‐ON/OFF), there was a reduction in cardiac hypertrophy and improvement in left ventricular failure.
Cardiac knockdown of SGLT1 in a murine model of PRKAG2 cardiomyopathy attenuates the disease phenotype, implicating SGLT1 in the pathogenesis. Overexpression of SGLT1 causes pathologic cardiac hypertrophy and left ventricular failure that is reversible. This is the first report of cardiomyocyte‐specific transgenic knockdown of a target gene.
PMCID: PMC4310371  PMID: 25092788
cardiomyopathy; glucose; heart failure; hypertrophy
20.  Health‐Related Quality of Life in Premature Acute Coronary Syndrome: Does Patient Sex or Gender Really Matter? 
Limited data exist as to the relative contribution of sex and gender on health‐related quality of life (HRQL) among patients with acute coronary syndrome (ACS). This study aims to evaluate the effect of sex and gender‐related variables on long‐term HRQL among young adults with ACS.
Methods and Results
GENESIS‐PRAXY (GENdEr and Sex determInantS of cardiovascular disease: from bench to beyond‐Premature Acute Coronary SYndrome) is a multicenter, prospective cohort study (January 2009 to August 2013) of adults aged 18 to 55 years, hospitalized with ACS. HRQL was measured at baseline, 1, 6, and 12 months using the Short Form‐12 and Seattle Angina Questionnaire (SAQ) among 1213 patients. Median age was 49 years. Women reported worse HRQL than men over time post‐ACS, both in terms of physical and mental functioning. Gender‐related factors were more likely to be predictors of HRQL than sex. Femininity score, social support, and housework responsibility were the most common gender‐related predictors of HRQL at 12 months. We observed an interaction between female sex and social support (β=0.44 [95% confidence interval, 0.01, 0.88]; P=0.047) for the physical limitation subscale of the SAQ.
Young women with ACS report significantly poorer HRQL than young men. Gender appears to be more important than sex in predicting long‐term HRQL post‐ACS. Specific gender‐related factors, such as social support, may be amenable to interventions and could improve the HRQL of patients with premature ACS.
PMCID: PMC4310372  PMID: 25074696
angina; cardiovascular diseases; myocardial infarction; sex
21.  Circulating Myeloid‐Related Protein–8/14 is Related to Thromboxane‐Dependent Platelet Activation in Patients With Acute Coronary Syndrome, With and Without Ongoing Low‐Dose Aspirin Treatment 
Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low‐dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11‐dehydro‐TXB2) is predictive of vascular events in high‐risk patients. Myeloid‐related protein (MRP)‐8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP‐14 has emerged as a powerful predictor of ACS.
Methods and Results
We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP‐8/14 release in the circulation is related to TX‐dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low‐dose aspirin–treated ACS patients. In ACS patients, plasma MRP‐8/14 and urinary 11‐dehydro‐TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin‐treated ACS patients, MRP‐8/14 and 11‐dehydro‐TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11‐dehydro‐TXB2 significantly predicted higher MRP‐8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R2=0.463 and adj R2=0.497) after multivariable adjustment. Conversely, plasma MRP‐8/14 (P<0.001) and higher urinary 8‐iso‐prostaglandin F2α (P=0.050) levels were significant predictors of residual, on‐aspirin, TX biosynthesis in ACS (adjusted R2=0.384).
Circulating MRP‐8/14 is associated with TX‐dependent platelet activation in ACS, even during low‐dose aspirin treatment, suggesting a contribution of residual TX to MRP‐8/14 shedding, which may further amplify platelet activation. Circulating MRP‐8/14 may be a target to test different antiplatelet strategies in ACS.
PMCID: PMC4310373  PMID: 25037196
acute coronary syndrome; aspirin; platelet‐derived factors; platelets; thromboxane
23.  B‐type Natriuretic Peptides for the Prediction of Cardiovascular Events in Patients With Stable Coronary Heart Disease: The Heart and Soul Study 
Brain‐type natriuretic peptide (BNP) and the amino‐terminal fragment of its prohormone (NT‐proBNP) are known predictors of cardiovascular outcomes in patients with coronary heart disease; however, the relative prognostic value of these 2 biomarkers for secondary events remains unclear.
Methods and Results
In 983 participants with stable coronary heart disease, we evaluated the association of BNP and NT‐proBNP with time to hospitalization for heart failure, nonfatal myocardial infarction, stroke or transient ischemic attack, cardiovascular death, and combined major adverse cardiovascular events (MACE). During an average follow‐up of 6.5±3.3 years, both BNP and NT‐proBNP were associated with increased risk of MACE in a multivariable‐adjusted model (hazard ratio per standard deviation of log BNP: 1.58; 95% CI: 1.32 to 1.89; hazard ratio per standard deviation of log NT‐proBNP: 1.84; 95% CI: 1.52 to 2.24). When added to traditional risk factors, NT‐proBNP predicted MACE better than BNP (C statistic: 0.76 versus 0.72, P<0.001). Similarly, the addition of NT‐proBNP resulted in a greater net reclassification improvement for predicting MACE than the addition of BNP (65% for NT‐proBNP, 56% for BNP).
Both BNP and NT‐proBNP were significant predictors of MACE in stable coronary heart disease; however, NT‐proBNP was superior to BNP for net risk reclassification for MACE.
PMCID: PMC4310375  PMID: 25053234
adverse cardiovascular outcomes; BNP; NT‐proBNP; risk assessment; stable coronary heart disease
24.  Activation of Endothelial Transient Receptor Potential C3 Channel Is Required for Small Conductance Calcium‐Activated Potassium Channel Activation and Sustained Endothelial Hyperpolarization and Vasodilation of Cerebral Artery 
Transient receptor potential C3 (TRPC3) has been demonstrated to be involved in the regulation of vascular tone through endothelial cell (EC) hyperpolarization and endothelium‐dependent hyperpolarization–mediated vasodilation. However, the mechanism by which TRPC3 regulates these processes remains unresolved. We tested the hypothesis that endothelial receptor stimulation triggers rapid TRPC3 trafficking to the plasma membrane, where it provides the source of Ca2+ influx for small conductance calcium‐activated K+ (SKCa) channel activation and sustained EC hyperpolarization.
Methods and Results
Pressurized artery studies were performed with isolated mouse posterior cerebral artery. Treatment with a selective TRPC3 blocker (Pyr3) produced significant attenuation of endothelium‐dependent hyperpolarization–mediated vasodilation and endothelial Ca2+ response (EC‐specific Ca2+ biosensor) to intraluminal ATP. Pyr3 treatment also resulted in a reduced ATP‐stimulated global Ca2+ and Ca2+ influx in primary cultures of cerebral endothelial cells. Patch‐clamp studies with freshly isolated cerebral ECs demonstrated 2 components of EC hyperpolarization and K+ current activation in response to ATP. The early phase was dependent on intermediate conductance calcium‐activated K+ channel activation, whereas the later sustained phase relied on SKCa channel activation. The SKCa channel–dependent phase was completely blocked with TRPC3 channel inhibition or in ECs of TRPC3 knockout mice and correlated with increased trafficking of TRPC3 (but not SKCa channel) to the plasma membrane.
We propose that TRPC3 dynamically regulates SKCa channel activation through receptor‐dependent trafficking to the plasma membrane, where it provides the source of Ca2+ influx for sustained SKCa channel activation, EC hyperpolarization, and endothelium‐dependent hyperpolarization–mediated vasodilation.
PMCID: PMC4310376  PMID: 25142058
cerebrovascular circulation; endothelium; endothelium‐derived factors; ion channels; vasculature
25.  Plasma Phospholipid Trans‐Fatty Acids Levels, Cardiovascular Diseases, and Total Mortality: The Cardiovascular Health Study 
While self‐reported trans–fatty acid (TFA) consumption is linked to coronary heart disease (CHD), relationships between objective biomarkers of TFA subtypes (t‐16:1n9, total t‐18:1, and cis/trans‐(c/t‐), t/c‐ and t/t‐18:2) and cardiovascular disease (CVD) or total mortality are not well established.
Methods and Results
We evaluated 2742 adults in the Cardiovascular Health Study, aged 74±5 years and free of prevalent CVD, with plasma phospholipid TFA measures in 1992. Incident fatal and nonfatal CHD events, CVD and non‐CVD mortality, and total mortality were centrally adjudicated through 2010. Risks were assessed using Cox proportional hazards. During 31 494 person‐years, 1735 total deaths and 639 total CHD events occurred. In the multivariate model including mutual adjustment for the 5 TFA subtypes, circulating t/t‐18:2 was associated with higher total mortality (extreme quintile hazard ratio (HR)=1.23, 95% CI=1.04 to 1.44, P‐trend=0.01), CVD mortality (HR=1.40, 95% CI=1.05 to 1.86, P‐trend=0.02), and total CHD (HR=1.39, 95% CI=1.06 to 1.83, P‐trend=0.01). t/c‐18:2 was positively related to total mortality (HR=1.19, P‐trend=0.05), total CHD (HR=1.67, P‐trend=0.002), and nonfatal CHD (HR=2.06, P‐trend=0.002) after mutual adjustment; these associations were insignificant without mutual adjustment. Neither t‐16:1n9 nor t‐18:1 was significantly associated with total mortality or CVD, nor was c/t‐18:2 if we excluded early cases.
Among circulating TFAs, t/t‐18:2 was most adversely associated with total mortality, mainly due to the increased risk of CVD. t/c‐18:2 was also positively associated with total mortality and CHD, but only after adjustment for other TFAs. These results highlight the need for further investigation of dietary sources, nondietary determinants, and health effects of specific TFA subtypes, especially t‐18:2 isomers.
PMCID: PMC4310377  PMID: 25164946
cardiovascular diseases; coronary disease; nutrition; total mortality; trans–fatty acids

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