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1.  Fish oil selectively improves heart function in a mouse model of lipid-induced cardiomyopathy 
Fish oil (FO) supplementation may improve cardiac function in some patients with heart failure, especially those with diabetes. To determine why this occurs, we studied the effects of FO in mice with heart failure due either to transgenic expression of the lipid uptake protein, acyl CoA synthetase 1 (ACS1) or overexpression of the transcription factor peroxisomal proliferator activated receptor (PPAR)γ via the cardiac specific myosin heavy chain (MHC) promoter. ACS1 mice and control littermates were fed three diets containing low or high-dose FO or non-purified diet (NPD) for 6 weeks. MHC-PPARγ mice were fed low-dose FO or NPD. Compared to control mice fed NPD, ACS1 and MHC-PPARγ mice fed NPD had reduced cardiac function and survival with cardiac fibrosis. In contrast, ACS1 mice fed high-dose FO had better cardiac function, survival and less myocardial fibrosis. FO increased eicosapentaenoic and docosahexaenoic acids and reduced saturated fatty acids in cardiac diacylglycerols. This was associated with reduced PKC alpha and beta activation. In contrast, low-dose FO reduced MHC-PPARγ mice survival with no change in PKC activation or cardiac function. Thus, dietary FO reverses fibrosis and improves cardiac function and survival of ACS1 mice, but does not benefit all forms of lipid-mediated cardiomyopathy.
PMCID: PMC3622223  PMID: 23567901
heart failure; diabetes; lipotoxicity; omega 3; fibrosis
2.  Lipoprotein lipase activity is required for cardiac lipid droplet production[S] 
Journal of Lipid Research  2014;55(4):645-658.
The rodent heart accumulates TGs and lipid droplets during fasting. The sources of heart lipids could be either FFAs liberated from adipose tissue or FAs from lipoprotein-associated TGs via the action of lipoprotein lipase (LpL). Because circulating levels of FFAs increase during fasting, it has been assumed that albumin transported FFAs are the source of lipids within heart lipid droplets. We studied mice with three genetic mutations: peroxisomal proliferator-activated receptor α deficiency, cluster of differentiation 36 (CD36) deficiency, and heart-specific LpL deletion. All three genetically altered groups of mice had defective accumulation of lipid droplet TGs. Moreover, hearts from mice treated with poloxamer 407, an inhibitor of lipoprotein TG lipolysis, also failed to accumulate TGs, despite increased uptake of FFAs. TG storage did not impair maximal cardiac function as measured by stress echocardiography. Thus, LpL hydrolysis of circulating lipoproteins is required for the accumulation of lipids in the heart of fasting mice.
PMCID: PMC3966699  PMID: 24493834
PPAR; Cd36; triglyceride
3.  Neuroimaging Findings in Cryptogenic Stroke Patients with and without PFO 
Patent foramen ovale (PFO) and cryptogenic stroke (CS) are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related etiology. We examined whether specific radiological findings are associated with PFO among subjects with CS and known PFO status.
We analyzed the Risk of Paradoxical Embolism (RoPE) database of subjects with CS and known PFO status, for associations between PFO and: 1) index stroke seen on imaging, 2) index stroke size, 3) index stroke location, 4) multiple index strokes, and 5) prior stroke on baseline imaging. We also compared imaging with purported “high risk” echocardiographic features.
Subjects (n=2680) were significantly more likely to have a PFO if their index stroke was large (OR 1.36, p=0.0025), seen on index imaging (OR 1.53, p=0.003), and superficially located (OR 1.54, p<0.0001). A prior stroke on baseline imaging was associated with not having a PFO (OR 0.66, p<0.0001). Finding multiple index strokes was unrelated to PFO status (OR 1.21, p=0.161). No echocardiographic variables were related to PFO status.
This is the largest study to report the radiological characteristics of patients with CS and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings.
PMCID: PMC3595100  PMID: 23339957
Patent Foramen Ovale; Cryptogenic Stroke; Imaging
4.  Left Atrial Volumes and Reservoir Function Are Associated With Subclinical Cerebrovascular Disease: The Cardiovascular Abnormalities and Brain Lesions (CABL) Study 
JACC. Cardiovascular imaging  2013;6(3):313-323.
To assess the relationship of left atrial (LA) phasic volumes and LA reservoir function with subclinical cerebrovascular disease in a stroke-free community-based cohort.
An increase in LA size is associated with cardiovascular events including stroke. However, it is not known whether LA phasic volumes and reservoir function are associated with subclinical cerebrovascular disease.
LA minimum (LAVmin) and maximum (LAVmax) volumes, and LA reservoir function, measured as total emptying volume (LAEV) and total emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography in 455 stroke-free participants from the community-based Cardiovascular Abnormalities and Brain Lesions (CABL) study. Subclinical cerebrovascular disease was assessed as silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV) by brain magnetic resonance imaging (MRI).
SBI prevalence was 15.4%; mean WMHV was 0.66±0.92%. Participants with SBI showed greater LAVmin (17.1±9.3 vs. 12.5±5.6 ml/m2, p<0.01) and LAVmax (26.6±8.8 vs. 23.3±7.0 ml/m2, p<0.01) compared to those without SBI. LAEV (9.5±3.4 vs. 10.8±3.9 ml/m2, p<0.01) and LAEF (38.7±14.7% vs. 47.0±11.9%, p<0.01) were also reduced in participants with SBI. In univariate analyses, greater LA volumes and smaller reservoir function were significantly associated with greater WMHV. In multivariate analyses, LAVmin remained significantly associated with SBI [adjusted odds ratio (OR) per SD increase: 1.37, 95% confidence intervals (CI) 1.04–1.80, p<0.05] and with WMHV (β=0.12, p<0.01), whereas LAVmax was not independently associated with either. Smaller LAEF was independently associated with SBI (adjusted OR=0.67, 95% CI 0.50–0.90, p<0.01) and WMHV (β=−0.09, p<0.05).
Greater LA volumes and reduced LA reservoir function are associated with subclinical cerebrovascular disease detected by brain MRI in subjects without history of stroke. LAVmin and LAEF, in particular, are more strongly associated with SBI and WMHV than the more commonly measured LAVmax, and their relationship with subclinical brain lesions is independent of other cardiovascular risk factors.
PMCID: PMC3600634  PMID: 23473112
Left atrial volume; Silent brain infarct; White matter hyperintensity volume; Magnetic resonance imaging; Three-dimensional echocardiography
5.  Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation 
Spinal muscular atrophy is a common motor neuron disease caused by low survival motoneuron (SMN), a key protein in the proper splicing of genes. Restoring the protein is therefore a promising therapeutic strategy. Implementation of this strategy, however, depends on defining the temporal requirements for SMN. Here, we used controlled knockdown of SMN in transgenic mice to determine the precise postnatal stage requirements for this protein. Reducing SMN in neonatal mice resulted in a classic SMA-like phenotype. Unexpectedly, depletion of SMN in adults had relatively little effect. Insensitivity to low SMN emerged abruptly at postnatal day 17, which coincided with establishment of the fully mature neuromuscular junction (NMJ). Mature animals depleted of SMN eventually exhibited evidence of selective neuromuscular pathology that was made worse by traumatic injury. The ability to regenerate the mature NMJ in aged or injured SMN-depleted mice was grossly impaired, a likely consequence of the inability to meet the surge in demand for motoneuronal SMN that was seen in controls. Our results demonstrate that relative maturity of the NMJ determines the temporal requirement for the SMN protein. These observations suggest that the use of potent but potentially deleterious SMN-enhancing agents could be tapered in human patients once the neuromuscular system matures and reintroduced as needed to enhance SMN for remodeling aged or injured NMJs.
PMCID: PMC3904626  PMID: 24463453
6.  Higher Ambulatory Blood Pressure is Associated with Aortic Valve Calcification in the Elderly-A Population-based Study 
Hypertension  2012;61(1):55-60.
Aortic valve calcification without outflow obstruction (stenosis) is common in the elderly and increases the risk of cardiovascular morbidity and mortality. Although high blood pressure (BP) measured at the doctor’s office is known to be associated with aortic valve calcification, little is known about the association between 24-hour ambulatory BP (ABP) and aortic valve calcification. Our objective was to clarify the association between ABP variables and aortic valve calcification. The study population consisted of 737 patients (mean age 71±9 years) participating in the Cardiovascular Abnormalities and Brain Lesions (CABL) study who underwent 24-hour ABP monitoring. Each aortic valve leaflet was graded on a scale of 0 (normal) to 3 (severe calcification). A total valve score (values 0–9) was calculated as the sum of all leaflets’ score. Advanced aortic valve calcification (score ≥4) was present in 77 subjects (10.4%). All systolic ABP variables (except systolic BP nocturnal decline) and mean asleep diastolic BP were positively associated with advanced calcification, while normal dipping status and diastolic BP nocturnal decline were negatively associated. Multiple regression analysis indicated that mean awake diastolic BP (OR 1.31, 95% CI 1.01–1.71) and asleep diastolic BP (OR 1.34, 95% CI 1.04–1.72) remained independently associated with advanced calcification after adjustment for age, sex, cigarette smoking, diabetes mellitus, hypercholesterolemia, hypertension, serum creatinine, and any degree of aortic insufficiency. Diastolic ABP is independently associated with advanced calcification. This finding may have important implications in gaining further insight into the mechanism of aortic valve calcification.
PMCID: PMC3521857  PMID: 23150510
ambulatory blood pressure; aortic valve calcification
7.  Polyplex-Microbubble Hybrids for Ultrasound-Guided Plasmid DNA Delivery to Solid Tumors 
Microbubble ultrasound contrast agents are being developed as image-guided gene carriers for targeted delivery in vivo. In this study, novel polyplex-microbubbles were synthesized, characterized and evaluated for systemic circulation and tumor transfection. Branched polyethylenimine (PEI; 25 kDa) was modified with polyethylene glycol (PEG; 5 kDa), thiolated and covalently attached to maleimide groups on lipid-coated microbubbles. The PEI-microbubbles demonstrated increasingly positive surface charge and DNA loading capacity with increasing maleimide content. The in vivo ultrasound contrast persistence of PEI-microbubbles was measured in the healthy mouse kidney, and a two-compartment pharmacokinetic model accounting for free and adherent microbubbles was developed to describe the anomalous time-intensity curves. The model suggested that PEI loading dramatically reduced free circulation and increased nonspecific adhesion to the vasculature. However, DNA loading to form polyplex-microbubbles increased circulation in the bloodstream and decreased nonspecific adhesion. PEI-microbubbles coupled to a luciferase bioluminescence reporter plasmid DNA were shown to transfect tumors implanted in the mouse kidney. Site-specific delivery was achieved using ultrasound applied over the tumor area following bolus injection of the DNA/PEI-microbubbles. In vivo imaging showed over 10-fold higher bioluminescence from the tumor region compared to untreated tissue. Ex vivo analysis of excised tumors showed greater than 40-fold higher expression in tumor tissue than non-sonicated control (heart) tissue. These results suggest that the polyplex-microbubble platform offers improved control of DNA loading and packaging suitable for ultrasound-guided tissue transfection.
PMCID: PMC3822338  PMID: 21945680
theranostic; ultrasound contrast agent; delivery vehicle; gene delivery; tumor; SKNEP-1; polyethylenimine; PEI; polyethylene glycol; PEG
8.  Abnormal p38α mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation 
Human Molecular Genetics  2012;21(19):4325-4333.
We previously interrogated the transcriptome in heart tissue from LmnaH222P/H222P mice, a mouse model of cardiomyopathy caused by lamin A/C gene (LMNA) mutation, and found that the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase branches of the mitogen-activated protein (MAP) kinase signaling pathway were abnormally hyperactivated prior to the onset of significant cardiac impairment. We have now used an alternative gene expression analysis tool to reanalyze this transcriptome and identify hyperactivation of a third branch of the MAP kinase cascade, p38α signaling. Biochemical analysis of hearts from LmnaH222P/H222P mice showed enhanced p38α activation prior to and after the onset of heart disease as well as in hearts from human subjects with cardiomyopathy caused by LMNA mutations. Treatment of LmnaH222P/H222P mice with the p38α inhibitor ARRY-371797 prevented left ventricular dilatation and deterioration of fractional shortening compared with placebo-treated mice but did not block the expression of collagen genes involved in cardiac fibrosis. These results demonstrate that three different branches of the MAP kinase signaling pathway with overlapping consequences are involved in the pathogenesis of cardiomyopathy caused by LMNA mutations. They further suggest that pharmacological inhibition of p38α may be useful in the treatment of this disease.
PMCID: PMC3441127  PMID: 22773734
9.  Arterial Stiffness and Wave Reflection: Sex Differences and Relationship with Left Ventricular Diastolic Function 
Hypertension  2012;60(2):362-368.
Increased arterial stiffness and wave reflection have been reported in heart failure with normal ejection fraction (HFNEF) and in asymptomatic left ventricular (LV) diastolic dysfunction, a precursor of HFNEF. It is unclear whether women, who have higher frequency of HFNEF, are more vulnerable than men to the deleterious effects of arterial stiffness on LV diastolic function. We investigated in a large community-based cohort, whether sex differences exist in the relationship between arterial stiffness, wave reflection and LV diastolic function. Arterial stiffness and wave reflection were assessed in 983 participants from the Cardiovascular Abnormalities and Brain Lesions (CABL) study using applanation tonometry. Central pulse pressure/stroke volume index (cPP/SVi), total arterial compliance, pulse pressure amplification and augmentation index were used as parameters of arterial stiffness and wave reflection. LV diastolic function was evaluated by two-dimensional echocardiography and tissue-Doppler imaging. Arterial stiffness and wave reflection were greater in women compared to men, independent of body size and heart rate (all p<0.01), and showed inverse relationships with parameters of diastolic function in both sexes. Further adjustment for cardiovascular risk factors attenuated these relationships; however, higher cPP/SVi predicted LV diastolic dysfunction in women [odds ratio (OR) 1.54, 95% confidence intervals (CI) 1.03–2.30] and men (OR: 2.09, 95% CI 1.30–3.39) independent of other risk factors. In conclusion, in our community-based cohort study, higher arterial stiffness was associated with worse LV diastolic function in men and women. Women’s higher arterial stiffness, independent of body size, may contribute to their greater susceptibility to develop HFNEF.
PMCID: PMC3402954  PMID: 22753223
Arterial stiffness; Wave reflection; Diastole; Sex; Echocardiography
10.  Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm 
The New England journal of medicine  2012;366(20):1859-1869.
It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm.
We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause.
The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82).
Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.
PMCID: PMC3723382  PMID: 22551105
Journal of cardiology  2010;56(2):134-141.
The presence of a patent foramen ovale has been found to be associated with an increased risk of ischemic stroke of otherwise unknown origin (cryptogenic stroke). The present article will review the evidence regarding this association, the technical aspects of PFO detection, and the preventive options to decrease the risk of recurrent cerebral events.
PMCID: PMC3723385  PMID: 20591626
12.  Temsirolimus activates autophagy and ameliorates cardiomyopathy caused by lamin A/C gene mutation 
Science translational medicine  2012;4(144):144ra102.
Mutations in the lamin A/C gene (LMNA) encoding A-type lamins cause a diverse range of diseases collectively called laminopathies, the most common of which is dilated cardiomyopathy. Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways but the specific mechanisms involved are poorly understood. Here we show that AKT-mTOR pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function. We also show defective autophagy in hearts of these mice and that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy. These findings provide a rationale for a novel treatment of LMNA cardiomyopathy and implicate defective autophagy as a pathogenic mechanism of cardiomyopathy arising from LMNA mutation.
PMCID: PMC3700376  PMID: 22837537
13.  Coronary Death and Myocardial Infarction among Hispanics in the Northern Manhattan Study: Exploring the Hispanic Paradox 
Annals of epidemiology  2012;22(5):303-309.
Prior studies have reported that Hispanics have lower cardiovascular disease (CVD) mortality despite a higher burden of risk factors. We examined whether Hispanic ethnicity was associated with a lower risk of nonfatal myocardial infarction (MI) coronary death (CD) and vascular death.
A total of 2671 participants in the Northern Manhattan Study without clinical CVD were prospectively evaluated. Cox models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association of race–ethnicity with nonfatal MI, CD, and vascular death after adjusting for demographic and CVD risk factors.
Mean age was 68.8 (10.4) years; 52.8% were Hispanic (88% Caribbean-Hispanic). Hispanics were more likely to have hypertension (73.1% vs. 62.2%, p < .001) and diabetes (22.0% vs. 13.3%, p < .001), and less likely to perform any physical activity (50.1% vs. 69.2%, p < .001) compared to non-Hispanic whites (NHW). During a mean 10 years of follow-up there were 154 nonfatal MIs, 186 CD, and 386 vascular deaths. In fully adjusted models, Hispanics had a lower risk of CD (adjusted HR = 0.36, 95% CI: 0.21–0.60), and vascular death (adjusted HR = 0.62, 95% CI: 0.43–0.89), but not nonfatal MI (adjusted HR = 0.95, 95% CI: 0.56–1.60) when compared to NHW.
We found a “Hispanic paradox” for coronary and vascular deaths, but not nonfatal MI.
PMCID: PMC3657757  PMID: 22424967
Hispanic; Paradox; Mortality; Cardiovascular Disease
14.  Relationship Between Ambulatory Blood Pressure and Aortic Arch Atherosclerosis 
Atherosclerosis  2012;221(2):427-431.
Atherosclerotic plaque in the aortic arch is an independent risk factor for ischemic stroke. Although high blood pressure (BP) measured at the doctor’s office is known to be associated with aortic atherosclerosis, little is known on the association between 24-hour ambulatory BP and aortic arch plaque presence and severity. Our objective was to clarify the association between ambulatory BP variables and aortic arch atherosclerosis in a community-based cohort.
The study population consisted of 795 patients (mean age 71±9 years) participating in the Cardiovascular Abnormalities and Brain Lesions (CABL) study who underwent 24-hour ambulatory BP monitoring (ABPM). Arch plaque was evaluated by 2D transthoracic echocardiography from a suprasternal window.
All systolic ABPM variables (24-hour/daytime/nighttime mean systolic BP, daytime/nighttime systolic BP variability) were associated with the presence of any plaque and large (≥4mm) plaque, whereas diastolic BP variables were not associated with aortic atherosclerosis. Multiple regression analysis indicated that nighttime systolic BP variability (expressed as the standard deviation of nighttime systolic BP) remained independently associated with large plaque after adjustment for age, sex, cigarette smoking, history of hypertension, diabetes mellitus, hypercholesterolemia, anti-hypertensive medication and nighttime mean systolic BP (odds ratio 1.39 per 1 standard deviation increase, 95% CI 1.00 to 1.93, P<0.05).
Systolic ABPM variables are significantly associated with the presence of arch plaque. Nighttime systolic BP variability is independently associated with large arch plaque. These findings may have important implications in gaining further insights into the mechanism of arch plaque formation and progression.
PMCID: PMC3312936  PMID: 22296886
ambulatory blood pressure; aortic arch atherosclerosis; blood pressure variability
15.  Mice with cardiac overexpression of PPARγ have impaired repolarization and spontaneous fatal ventricular arrhythmias (Morrow, PPARγ overexpression induces fatal arrhythmias) 
Circulation  2011;124(25):2812-2821.
Diabetes and obesity, which confer an increased risk of sudden cardiac death, are associated with cardiomyocyte lipid accumulation and altered cardiac electrical properties, manifested by prolongation of the QRS duration and QT interval. It is difficult to distinguish the contribution of cardiomyocyte lipid accumulation versus the contribution of global metabolic defects to the increased incidence of sudden death and electrical abnormalities.
Methods and Results
In order to study the effects of metabolic abnormalities on arrhythmias without the complex systemic effects of diabetes and obesity, we studied cardiac-specific transgenic mice expressing PPARγ1 via the cardiac α-myosin heavy-chain promoter. The PPARγ-transgenic mice develop abnormal accumulation of intracellular lipids and die as young adults, prior to a significant reduction in systolic function. Using implantable ECG telemeters, we found that these mice have prolongation of the QRS and QT intervals, and spontaneous ventricular arrhythmias, including polymorphic ventricular tachycardia and ventricular fibrillation. Isolated cardiomyocytes demonstrated prolonged action potential duration caused by reduced expression and function of the potassium channels responsible for repolarization. Short-term exposure to pioglitazone, a PPARγ agonist, had no effect on mortality or rhythm in WT mice, but further exacerbated the arrhythmic phenotype and increased the mortality in the PPARγ TG mice.
Our findings support an important link between PPARγ activation, cardiomyocyte lipid accumulation, ion channel remodeling and increased cardiac mortality.
PMCID: PMC3258098  PMID: 22124376
arrhythmia; metabolism; ion channels
16.  Alcohol Consumption and Atherosclerotic Burden in the Proximal Thoracic Aorta 
Atherosclerosis  2011;219(2):794-798.
The relationship between alcohol consumption and ischemic stroke or aortic atherosclerosis is unclear, but a protective effect of moderate consumption on stroke risk has been suggested. We conducted a cross-sectional analysis in a population-based sample to evaluate the possible association between alcohol consumption and aortic atherosclerotic plaque (AAP), which is associated with increased stroke risk.
As part of the NINDS-funded Aortic Plaques and Risk of Ischemic Stroke (APRIS) study, 464 subjects over the age of 55 were studied (mean age 69.1±9.0 with 251 males and 213 females), including 255 patients with first ischemic stroke and 209 stroke-free controls. Transesophageal echocardiogram was performed for the detection of AAP. Alcohol consumption was measured in number of drinks per week during the previous year using a standardized questionnaire, and categorized as: (1) none or minimal (<1 drink per month); (2) light to moderate (between 1 drink per month and 2 drinks daily); and (3) heavy (>2 daily). Multivariate conditional logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence interval (CI) for alcohol consumption and AAP after adjustment for the potential confounding risk factors (age, sex, hypertension, diabetes, dyslipidemia, and cigarette smoking).
Overall, AAP were detected in 326 subjects (70.4%), and 174 subjects (37.6%) had AAP ≥ 4mm, which carry higher stroke risk. No or minimal alcohol consumption was present in 241 subjects (53.2%), and 177 subjects (39.0%) had light to moderate consumption. Prevalence of light to moderate alcohol consumption was significantly lower in stroke patients than in controls (35.5% vs. 60.3%, p<0.001) and in subjects who had AAP compared with those without it (41.6% vs. 58.8%, p=0.008). After adjusting for significant predictors of atherosclerosis, alcohol consumption of any degree was inversely associated with AAP (OR 0.61; 95%CI 0.37–0.98, p=0.042). The significance of the association was borderline for AAP ≥ 4mm (OR 0.64, 95%CI 0.41–1.00, p=0.054). In the dose-response analysis, only light to moderate alcohol consumption was significantly associated with a lower risk of having any AAP (adjusted OR 0.45; 95%CI 0.29–0.68, p<0.001) or AAP ≥ 4mm (adjusted OR 0.51; 95%CI 0.34–0.77, p=0.001).
Our data indicate that light to moderate alcohol consumption is associated with lower atherosclerotic burden in the proximal aortic arch. This observation may explain at least in part the lower risk of ischemic stroke observed in moderate alcohol consumers.
PMCID: PMC3228516  PMID: 21885050
aorta; atherosclerosis; stroke; alcohol drinking; risk factors
17.  Cardiomyocyte Aldose Reductase Causes Heart Failure and Impairs Recovery from Ischemia 
PLoS ONE  2012;7(9):e46549.
Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the α–myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism. These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure.
PMCID: PMC3459912  PMID: 23029549
18.  Effects of Continuous- Versus Pulsatile-Flow Left Ventricular Assist Devices on Myocardial Unloading and Remodeling 
Circulation. Heart failure  2011;4(5):546-553.
Continuous-flow left ventricular assist devices (LVAD) are increasingly used for patients with end-stage heart failure (HF). We analyzed the effects of ventricular decompression by continuous- versus pulsatile-flow LVADs on myocardial structure and function in this population.
Methods and Results
Sixty-one patients who underwent LVAD implantation as bridge-to-transplant were analyzed (pulsatile-flow LVAD: Group P, n=31; continuous-flow LVAD: Group C, n=30). Serial echocardiograms, serum levels of brain natriuretic peptide (BNP) and extracellular matrix biomarkers (ECM) were compared between the groups. Myocardial BNP and ECM gene expression were evaluated in a subset of 18 patients. Postoperative left ventricular (LV) ejection fraction was greater (33.2±12.6 vs. 17.6±8.8%, p<0.0001) and the mitral E/E′ was lower (9.9±2.6 vs. 13.2±3.8, p=0.0002) in Group P versus Group C. Postoperative serum levels of BNP, metalloproteinases (MMP)-9 and tissue inhibitor of MMP (TIMP)-4 were significantly lower in Group P compared to Group C (BNP: 552.6±340.6 vs. 965.4±805.7 pg/mL, p<0.01; MMP9: 309.0±220.2 vs. 475.2±336.9 ng/dL, p<0.05; TIMP4: 1490.9±622.4 vs. 2014.3±452.4 ng/dL, p<0.001). Myocardial gene expression of ECM markers and BNP decreased in both groups; however, expression of TIMP-4 decreased only in Group P (p=0.024).
Mechanical unloading of the failing myocardium using pulsatile devices is more effective as indicated by echocardiographic parameters of systolic and diastolic LV function as well as dynamics of BNP and ECM markers. Therefore, specific effects of pulsatile mechanical unloading on the failing myocardium may have important implications for device selection especially for the purpose of bridge-to-recovery in patients with advanced HF.
PMCID: PMC3178740  PMID: 21765125
echocardiography; heart failure; heart-assist device; transplant; remodeling
19.  Left atrial minimum volume and reservoir function as correlates of left ventricular diastolic function: impact of left ventricular systolic function 
Heart  2012;98(10):813-820.
Left atrial (LA) maximum volume (LAVmax) is an indicator of left ventricular (LV) diastolic function. However, LAVmax is also influenced by systolic events, whereas the LA minimum volume (LAVmin) is directly exposed to LV pressure. The authors hypothesised that LAVmin may be a better correlate of LV diastolic function than LAVmax.
University hospital.
357 participants from a community-based cohort study.
LA volumes and reservoir function, measured as total LA emptying volume (LAEV) and LA emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography. LV diastolic function was assessed by trans-mitral early (E) and late (A) Doppler velocities and mitral early diastolic velocity by tissue-Doppler (e′). LV systolic function was assessed by LV ejection fraction (LVEF) and global longitudinal strain (GLS) by speckle-tracking.
LAVmin significantly increased with worsening diastolic dysfunction (p<0.001), whereas the increase in LAVmax was less pronounced (p=0.07). LAEV and LAEF decreased with worsening diastolic dysfunction (both p<0.001). In linear regressions, LAVmin and LAVmax were significant predictors of E/e′, with higher parameter estimates for LAVmin. In multivariate models, LAVmin resulted strongly associated with E/e′ (β=0.45, p<0.001), whereas LAVmax was not (β=− 0.16, p=0.08). LA reservoir function was better associated with GLS than LVEF. In multivariate analyses, GLS was significantly associated with LAVmax (β=− 0.15, p=0.002), LAEV (β=−0.37, p<0.001) and LAEF (β=−0.28, p<0.001) but not with LAVmin.
LAVmin is a better correlate of LV diastolic function than LAVmax. The impact of LV longitudinal systolic function on LA reservoir function might explain the weaker relation between LAVmax and LV diastolic function.
PMCID: PMC3392716  PMID: 22543839
20.  Race-ethnic differences in the relationship between lipid profile components and risk of myocardial infarction: the Northern Manhattan Study 
American heart journal  2011;161(5):886-892.
To explore race-ethnic differences in the relationship between plasma lipid components and risk of incident myocardial infarction (MI).
As part of the Northern Manhattan Study, 2738 community residents without cardiovascular disease were prospectively evaluated. Baseline fasting blood samples were collected and lipid panel components were analyzed as continuous and categorical variables. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for incident MI after adjusting for demographic and cardiovascular risk factors.
The mean age was 68.8±10.4 years; 36.7% men, 19.9% non-Hispanic white, 24.9% non-Hispanic black, and 52.8% Hispanic (over 80% from the Caribbean). Hispanics had lower mean HDL-C, and higher TG/HDL-C. During a mean 8.9 years of follow-up there were 163 incident MIs. In the whole cohort all lipid profile components were associated with risk of MI in the expected directions. However, HDL-C (adjusted HR per 10 mg/dl increase 0.93, 95%CI 0.76–1.12) and TG/HDL-C>2 (adjusted HR 0.89, 95%CI 0.51–1.55) were not predictive of MI among Hispanics, but were predictive among non-Hispanic blacks and whites. TG/HDL-C per unit increase was associated with an 8% higher risk of MI among Hispanics (adjusted HR 1.08, 95%CI 1.04–1.12).
In Hispanics, low HDL-C and TG/HDL-C>2 were not associated with MI risk. Our data suggests that a different TG/HDL ratio cutoff may be needed among Hispanics to predict MI risk.
PMCID: PMC3095911  PMID: 21570518
21.  Effect of Obesity and Overweight on Left Ventricular Diastolic Function: a Community-based Study in an Elderly Cohort 
To assess the independent effect of increased body size on left ventricular (LV) diastolic function.
Obese and overweight individuals are at increased risk of heart failure. LV diastolic dysfunction is an asymptomatic condition associated with future heart failure. It is unclear whether obesity and overweight are independently associated with LV diastolic dysfunction.
LV diastolic function was evaluated in 950 participants from the Cardiovascular Abnormalities and Brain Lesions (CABL) study by traditional and tissue-Doppler imaging. Peak early and late trans-mitral diastolic flow velocities (E, A) and early diastolic mitral annulus velocity (E′) were measured, and E/A and E/E′ were calculated. The study sample was divided into three groups: normal weight [body mass index (BMI)<25.0], overweight (BMI 25.0–29.9) and obese (BMI≥30).
In multivariate analyses, BMI was independently associated with higher E, A, and E/E′, an indicator of LV filling pressure (all p≤0.01). Overweight and obese had lower E′ (both p<0.01) and higher E/E′ (both p<0.01) than normal weight participants. E/A was lower in obese than normal weight subjects (p<0.01). The risk of diastolic dysfunction was significantly higher in overweight (adjusted odds ratio: 1.52, 95% confidence intervals 1.04–2.22) and obese (adjusted odds ratio: 1.60, 95% confidence intervals 1.06–2.41) compared to normal weight individuals.
Increased BMI was associated with worse LV diastolic function independent of LV mass and associated risk factors. The increased risk of LV diastolic dysfunction in both overweight and obese individuals may partially account for the increased risk of heart failure associated with both conditions.
PMCID: PMC3077126  PMID: 21414533
obesity; overweight; diastolic dysfunction; echocardiography; risk factors
22.  Arterial Wave Reflection and Subclinical Left Ventricular Systolic Dysfunction 
Journal of hypertension  2011;29(3):574-582.
Increased arterial wave reflection is a predictor of cardiovascular events and has been hypothesized to be a cofactor in the pathophysiology of heart failure. Whether increased wave reflection is inversely associated with left ventricular (LV) systolic function in subjects without heart failure is not clear.
Arterial wave reflection and LV systolic function were assessed in 301 participants from the Cardiovascular Abnormalities and Brain Lesions (CABL) study using 2-dimensional echocardiography and applanation tonometry of the radial artery to derive central arterial waveform by a validated transfer function. Aortic augmentation index (AIx) and wasted energy index (WEi) were used as indices of wave reflection. LV systolic function was measured by ejection fraction (LVEF) and tissue Doppler imaging (TDI). Mitral annulus peak systolic velocity (Sm), peak longitudinal strain and strain rate were measured. Participants with history of coronary artery disease, atrial fibrillation, LVEF <50% or wall motion abnormalities were excluded.
Mean age of the study population was 68.3±10.2 years (64.1% women, 65% hypertensive). LV systolic function by TDI was lower with increasing wave reflection, whereas LVEF was not. In multivariate analysis, TDI parameters of LV longitudinal systolic function were significantly and inversely correlated to AIx and WEi (p values from 0.05 to 0.002).
In a community cohort without heart failure and with normal LVEF, an increased arterial wave reflection was associated with subclinical reduction in LV systolic function assessed by novel TDI techniques. Further studies are needed to investigate the prognostic implications of this relationship.
PMCID: PMC3039083  PMID: 21169863
wave reflection; arterial stiffness; systolic function; strain; strain rate; tissue Doppler; echocardiography
23.  Association between Social Isolation and Left Ventricular Mass 
The American journal of medicine  2011;124(2):164-170.
Social isolation is associated with progression of cardiovascular disease with the most socially isolated patients being at increased risk. Increased left ventricular mass is a predictor of cardiovascular morbidity and mortality. It is not yet clear whether social isolation is a determinant of increased left ventricular mass.
We performed a cross-sectional study of Northern Manhattan Study participants who were free of clinical cardiovascular disease, had obtained transthoracic echocardiograms (n=2021) and a baseline questionnaire on social habits. Social isolation was defined as the lack of friendship networks (knowing fewer than 3 people well enough to visit within their homes). Echocardiographic left ventricular mass was indexed to height2.7, analyzed as a continuous variable and compared between exposure groups.
The prevalence of social isolation was 13.5%. The average left ventricular mass was significantly higher (50.2 gm/m2.7) in those who were, as compared to those who were not (47.6 gm/m2.7), socially isolated (p<0.05). Higher prevalence of social isolation was found among those less educated, uninsured or unemployed.There were no significant race-ethnic differences in the prevalence of social isolation. In multivariate analysis, there was a trend toward an association between social isolation and increased left ventricular mass in the total cohort (p=0.09). Among Hispanics, social isolation was significantly associated with greater left ventricular mass. Hispanics who were socially isolated averaged 3.9 gm/ht2.7 higher left ventricular mass compared to those not socially isolated (p=0.002). This relationship was not present among non-Hispanic blacks or whites.
In this urban tri-ethnic cohort, social isolation was prevalent and associated with indices of low socioeconomic status. Hispanics who were socially isolated had a greater risk for increased left ventricular mass.
PMCID: PMC3064505  PMID: 21295196
social isolation; left ventricular mass; Hispanics; psychosocial factors
24.  Septal Pouch in the Left Atrium and Risk of Ischemic Stroke: A Case-Control Study 
JACC. Cardiovascular imaging  2010;3(12):1276-1283.
We sought to assess the association between the presence of a septal pouch in the left atrium and ischemic stroke.
Recently, a new anatomical entity, named a left septal pouch (LSP), was described in a pathology study. It was suggested that the presence of LSP may favor the stasis of blood and possibly result in thromboembolic complications. However, the embolic potential of a LSP is not known.
The association between LSP and risk of stroke was assessed using a population-based case-control study design. The presence of LSP was assessed by transesophageal echocardiography in 187 patients over age 50 with first-ever ischemic stroke (96 men, mean age 70.6 ± 9.0 years) and in 157 control subjects matched to patients by age, sex, and race/ethnicity. The association between LSP and risk of stroke was assessed after adjustment for other stroke risk factors.
Patients with LSPs were younger (67.5 ± 9.1 vs. 69.6 ± 8.8; p=0.046) and had a lower proportion of hypertension (68.0% vs. 80.3%; p=0.01). There were no difference in the prevalence of LSP between stroke patients and control subjects (28.9% vs. 29.3%; p=0.93). The subgroup of 69 patients (36.9%) with crytptogenic stroke showed a similar prevalence of LSP (31.9% vs. 29.3%; p=0.70). Multivariable analysis showed that the presence of LSP was not associated with ischemic stroke (OR 1.09, 95% CI 0.64 to 1.85) or cryptogenic stroke (OR 1.41, 95% CI 0.71 to 2.78).
This study does not demonstrate evidence for association of the presence of LSP with ischemic stroke, or with cryptogenic stroke. The stroke risk associated with LSP may still require further evaluation in the younger stroke populations. The possibility that associated cofactors that may turn LSP from an innocent bystander into a causative mechanism for stroke remain to be elucidated.
PMCID: PMC3051190  PMID: 21163457
stroke; septal pouch; left atrium; transesophageal echocardiography
25.  Cardiomyocyte Triglyceride Accumulation and Reduced Ventricular Function in Mice with Obesity Reflect Increased Long Chain Fatty Acid Uptake and De Novo Fatty Acid Synthesis 
Journal of Obesity  2011;2012:205648.
A nonarteriosclerotic cardiomyopathy is increasingly seen in obese patients. Seeking a rodent model, we studied cardiac histology, function, cardiomyocyte fatty acid uptake, and transporter gene expression in male C57BL/6J control mice and three obesity groups: similar mice fed a high-fat diet (HFD) and db/db and ob/ob mice. At sacrifice, all obesity groups had increased body and heart weights and fatty livers. By echocardiography, ejection fraction (EF) and fractional shortening (FS) of left ventricular diameter during systole were significantly reduced. The Vmax for saturable fatty acid uptake was increased and significantly correlated with cardiac triglycerides and insulin concentrations. Vmax also correlated with expression of genes for the cardiac fatty acid transporters Cd36 and Slc27a1. Genes for de novo fatty acid synthesis (Fasn, Scd1) were also upregulated. Ten oxidative phosphorylation pathway genes were downregulated, suggesting that a decrease in cardiomyocyte ATP synthesis might explain the decreased contractile function in obese hearts.
PMCID: PMC3216284  PMID: 22132320

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