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1.  Depletion of extracellular signal-regulated kinase 1 in mice with cardiomyopathy caused by lamin A/C gene mutation partially prevents pathology before isoenzyme activation 
Human Molecular Genetics  2013;23(1):1-11.
Mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins cause dilated cardiomyopathy with variable muscular dystrophy. These mutations enhance mitogen-activated protein kinase signaling in the heart and pharmacological inhibition of extracellular signal-regulated kinase (ERK) 1 and 2 improves cardiac function in LmnaH222P/H222P mice. In the current study, we crossed mice lacking ERK1 to LmnaH222P/H222P mice and examined cardiac performance and survival. Male LmnaH222P/H222P/Erk1−/− mice lacking ERK1 had smaller left ventricular end systolic diameters and increased fractional shortening (FS) at 16 weeks of age than LmnaH222P/H222P/Erk1+/+ mice. Their mean survival was also significantly longer. However, the improved cardiac function was abrogated at 20 weeks of age concurrent with an increased activity of ERK2. LmnaH222P/H222P/Erk1−/− mice treated with an inhibitor of ERK1/2 activation had smaller left ventricular diameters and increased FS at 20 weeks of age. These results provide genetic evidence that ERK1 and ERK2 contribute to the development of cardiomyopathy caused by LMNA mutations and reveal interplay between these isoenzymes in maintaining a combined pathological activity in heart.
PMCID: PMC3857940  PMID: 23933734
2.  Transesophageal Echocardiography in Cryptogenic Stroke and PFO: The Analysis of Putative High Risk Features from the Risk of Paradoxical Embolism (RoPE) Database 
Patent foramen ovale (PFO) is associated with cryptogenic stroke (CS), though the pathogenicity of a discovered PFO in the setting of CS is typically unclear. Transesophageal echocardiography (TEE) features such as PFO size, an associated hypermobile septum, and presence of a right-to-left shunt at rest have all been proposed as markers of risk. The association of these TEE features with other markers of pathogenicity has not been examined.
Methods and Results
We used a recently derived score based on clinical and neuroimaging features to stratify patients with PFO and CS by the probability that their stroke is PFO-attributable. We examined whether high risk TEE features are seen more frequently in patients more likely to have had a PFO-attributable stroke (n = 637) compared to those less likely to have a PFO attributable stroke (n = 657). Large physiologic shunt size was not more frequently seen among those with probable PFO-attributable strokes (OR=0.92; p = 0.53). Neither the presence of a hypermobile septum nor a right-to-left shunt at rest were detected more often in those with a probable PFO-attributable stroke (OR=0.80; p = 0.45 and OR=1.15; 0.11 respectively).
We found no evidence that the proposed TEE risk markers of large PFO size, hypermobile septum, and presence of right-to-left shunt at rest are associated with clinical features suggesting that a CS is PFO-attributable. Additional tools to describe PFOs may be useful in helping to determine whether an observed PFO is incidental or pathogenically related to CS.
PMCID: PMC3934652  PMID: 24214884
cerebrovascular disease/stroke; echocardiography; cardiovascular imaging; risk factor; congenital heart disease
3.  Pre-operative echocardiographic features associated with persistent mitral regurgitation after left ventricular assist device implantation 
Previous studies have shown remarkable decrease in size of the left ventricle after left ventricular assist device (LVAD) implantation due to mechanical unloading. However, a certain number of patients continue to have significant mitral regurgitation (MR) under LVAD support. We investigated pre-operative echocardiographic features associated with persistent MR after LVAD implantation.
We retrospectively reviewed 82 consecutive patients undergoing continuous-flow LVAD implantation between 2007 and 2010. We obtained echocardiograms performed within 2 weeks before and 1 week after surgery. We investigated the pre operative echocardiographic findings associated with significant MR post-LVAD and compared 1-year mortality after LVAD surgery between patients with and without significant MR post-LVAD.
MR was significant in 43 patients (52.4%) before LVAD surgery. Among those, 5 underwent concomitant mitral valve repair (MVr) at the time of LVAD implantation. Of the remaining 38 patients, 25 (65.8%) showed improvement of MR, whereas 13 patients (34.2%) continued to have significant MR post-LVAD. Multivariate analysis revealed that posterior displacement of the coaptation point of mitral leaflets was significantly associated with significant MR post-LVAD (hazard ratio, 1.335; 95% confidence interval, 1.035–1.721; p = 0.026) even after adjusting for the amount of pre operative MR flow. Post-LVAD 1-year survival of patients with and without significant MR post-LVAD was not significantly different (92.3% vs 89.1%, p = 0.826).
Pre-LVAD posterior displacement of mitral leaflets may be indicative of post-operative significant MR, which would help identify echocardiographic features of functional MR refractory to simple volume reduction of the ventricle.
PMCID: PMC4278424  PMID: 23850122
heart failure; mitral regurgitation; ventricular assist device; echocardiography
4.  Stroke in Heart Failure in Sinus Rhythm: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial 
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses.
We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions.
Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3–5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups.
The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.
PMCID: PMC4256381  PMID: 23921215
Aspirin; Cardiac embolism; Heart failure; Stroke prevention
5.  Cognitive Function in Ambulatory Patients with Systolic Heart Failure: Insights from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial 
PLoS ONE  2014;9(11):e113447.
We sought to determine whether cognitive function in stable outpatients with heart failure (HF) is affected by HF severity. A retrospective, cross-sectional analysis was performed using data from 2, 043 outpatients with systolic HF and without prior stroke enrolled in the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial. Multivariable regression analysis was used to assess the relationship between cognitive function measured using the Mini-Mental Status Exam (MMSE) and markers of HF severity (left ventricular ejection fraction [LVEF], New York Heart Association [NYHA] functional class, and 6-minute walk distance). The mean (SD) for the MMSE was 28.6 (2.0), with 64 (3.1%) of the 2,043 patients meeting the cut-off of MMSE <24 that indicates need for further evaluation of cognitive impairment. After adjustment for demographic and clinical covariates, 6-minute walk distance (β-coefficient 0.002, p<0.0001), but not LVEF or NYHA functional class, was independently associated with the MMSE as a continuous measure. Age, education, smoking status, body mass index, and hemoglobin level were also independently associated with the MMSE. In conclusion, six-minute walk distance, but not LVEF or NYHA functional class, was an important predictor of cognitive function in ambulatory patients with systolic heart failure.
PMCID: PMC4245133  PMID: 25426862
6.  Benefit of Warfarin Compared With Aspirin in Patients With Heart Failure in Sinus Rhythm 
Circulation. Heart failure  2013;6(5):988-997.
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin.
Methods and Results
We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P=0.03).
In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.
Clinical Trial Registration
URL: Unique identifier: NCT00041938.
PMCID: PMC4242511  PMID: 23881846
aspirin; heart failure; sinus rhythm; stroke; warfarin
8.  Enhanced Efferocytosis of Apoptotic Cardiomyocytes Through MER Tyrosine Kinase Links Acute Inflammation Resolution to Cardiac Repair After Infarction 
Circulation research  2013;113(8):10.1161/CIRCRESAHA.113.301198.
Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. Following myocardial infarction (MI), phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes (CMs). The molecular mechanisms of efferocytosis of CMs and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function.
We set out to identify mechanisms of dying cardiomyocyte (CM) engulfment by phagocytes and to for the first time assess the causal significance of disrupting efferocytosis during MI.
Methods and Results
In contrast to other apoptotic cell receptors, macrophage MER tyrosine kinase (MER-TK) was necessary and sufficient for efferocytosis of CMs ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic CMs, independent of changes in non-CMs, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk; reciprocal transplantation of Mertk+/+ marrow into Mertk-/- mice corrected systolic dysfunction. Interestingly, an inactivated form of MERTK, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of MERTK inactivation post MI.
These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.
PMCID: PMC3840464  PMID: 23836795
Myocardial infarction; inflammation; macrophage; efferocytosis
9.  Relation Between Long Sleep and Left Ventricular Mass (from a Multiethnic Elderly Cohort) 
The American journal of cardiology  2013;112(4):599-603.
Short-sleep and long-sleep duration are associated with prevalent hypertension, poor cardiovascular health, and mortality. The relation of sleep hours with increased left ventricular (LV) mass, a strong correlate of elevated blood pressure (BP) values, is not established. We conducted a cross-sectional analysis among the participants of the population-based Cardiovascular Abnormalities and Brain Lesions study. LV mass was estimated by transthoracic echocardiography. Sleep duration was assessed by reported hours of sleep on a diary kept during 24-hour BP monitoring. Multivariate linear regression models were constructed to assess the relation between sleep hours and LV mass index (LV mass divided by body surface area). Analysis of sleep hour categories (short and long sleep) was performed. Among 756 participants (mean age 71 ± 9 years, 60% women, and 71% Hispanics), the mean sleep duration was 8.6 ± 1.8 hours, and LV mass index was 103 ± 26 g/m2. A J-shaped relation between sleep hours squared and LV mass index was observed adjusting for demographics and cardiovascular risk factors. Categorical analysis showed an association between long-sleep duration (>11 hours) and LV mass index (β = 7.4; p = 0.013). Long sleepers had higher diurnal systolic BP (p = 0.012) and nocturnal systolic BP (p <0.001) compared with the reference group. A great part of the variance between sleep duration and LV mass was explained by 24-hour systolic BP (β = 0.45; p <0.0001). In conclusion, self-reported long-sleep duration was associated with increased LV mass. Higher systolic BP, especially nocturnal, may account for part of the observed association.
PMCID: PMC3770129  PMID: 23711813
10.  An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke 
Neurology  2013;81(7):619-625.
We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO.
Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates.
Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%–26%) in those with 0 to 3 points to 73% (95% CI: 66%–79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%–28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%–4%) in the highest.
Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.
PMCID: PMC3775694  PMID: 23864310
11.  Risk Stratification of Ambulatory Patients with Advanced Heart Failure Undergoing Evaluation for Heart Transplantation 
Risk stratification of ambulatory heart failure (HF) patients has relied upon peak VO2 (pVO2) <14 mL/min/kg. We investigated whether additional clinical variables might further specify risk of death, ventricular assist device (VAD) implantation (INTERMACS<4) or heart transplantation (HTx; Status 1A or 1B) within one-year after HTx evaluation. We hypothesized that right ventricular stroke work index (RVSWI), pulmonary capillary wedge pressure (PCWP) and the Model for End-stage Liver Disease-Albumin score (MELD-A) would be additive prognostic predictors.
We retrospectively collected data on 151 ambulatory patients undergoing HTx evaluation. Primary outcomes were defined as HTx, LVAD or death within one-year following evaluation.
Our cohort was 54.9±11.1 year-old, 79.1% male, 37.6% with ischemic etiology (LVEF 21±11% and pVO2 12.6±3.5ml/min/kg). Fifty outcomes (33.1%) occurred (27 HTx, 15 VAD, and 8 deaths). Univariate logistic regression showed significant association of RVSWI (mmHg-L/m2) (OR0.47, p=0.036), PCWP (mmHg) (OR2.65, p=0.007), and MELD-A (OR2.73, p=0.006) with one-year events. Stepwise regression showed independent correlation of RVSWI<5 (OR6.70; p<0.01), PCWP>20 (OR5.48; p<0.01), MELD-A>14 (OR3.72; p<0.01) and pVO2<14 (OR3.36; p=0.024) with one-year events. A scoring system was composed with MELD-A>14 and pVO2<14, 1 point each, and PCWP>20 and RVSWI<5, 2 points each. A cutoff at 4 demonstrated a 54% sensitivity and 88% specificity for one-year events.
Ambulatory HF patients have significant one-year event rates. Risk stratification based on exercise performance, left-sided congestion, right ventricular dysfunction and liver congestion allows prediction of one-year prognosis. This study endorses early and timely referral for VAD and/or transplant.
PMCID: PMC4119928  PMID: 23415315
heart failure; prognosis; risk stratification
12.  Relationship of Multidirectional Myocardial Strain with Radial Thickening and Ejection Fraction and Impact of Left Ventricular Hypertrophy. A Study in a Community-Based Cohort 
Left ventricular (LV) systolic strain provides additional prognostic value to LV ejection fraction (LVEF) and wall motion analysis. However, the relationship between myocardial multidirectional strain and LVEF, and the effect of LV hypertrophy on this relationship, are not completely understood especially in unselected populations.
LV global longitudinal (εL) and circumferential (εC) systolic strain analysis was performed by two-dimensional speckle-tracking echocardiography in 215 participants from a community-based study. LV radial wall thickening was measured as global radial strain (εR), and LVEF was assessed by biplane Simpson’s method.
εR was significantly associated with εC (β=−0.56, p<0.01) and with εL (β= −0.18, p<0.01). The contribution of εL to εR was especially evident in subjects with lower εC and in presence of LV hypertrophy (β= −0.30, p<0.01). εL and εC were significantly associated with LVEF (β= −0.36 and β=−0.49, both p<0.01) independent of LV mass and other confounders, and their interaction significantly improved the prediction of LVEF (R-square change=0.14) but not of εR (R-square change=0.002).
εR is mainly related to εC with a smaller contribution of εL, which becomes especially evident in subjects with lower εC and in presence of LV hypertrophy. Therefore, radial thickening may not detect subclinical LV longitudinal function reduction in normal ventricles and when εC is preserved. While a reduction in εL has a limited impact on εR, it exerts a greater effect on global LVEF, therefore for a more accurate LVEF prediction both εL and εC need to be considered.
PMCID: PMC3640730  PMID: 23360509
Left ventricle; Systolic function; Strain; Ejection fraction; Speckle-tracking; Echocardiography
13.  Stroke Location and Association With Fatal Cardiac Outcomes 
Background and Purpose
Cardiac mortality after stroke is common, and small studies have suggested an association of short-term cardiac mortality with insular location of cerebral infarction. Few population-based studies with long-term follow-up have evaluated the effect of stroke location on the long-term risk of cardiac death or myocardial infarction (MI) after first ischemic stroke. We sought to determine the association between stroke location and cardiac death or MI in a multiethnic community-based cohort.
The Northern Manhattan Study is a population-based study designed to determine stroke incidence, risk factors, and prognosis in a multiethnic urban population. First ischemic stroke patients age 40 or older were prospectively followed up for cardiac death defined as fatal MI, fatal congestive heart failure, or sudden death/arrhythmia and for nonfatal MI. Primary brain anatomic site was determined by consensus of research neurologists. Hazard ratios (HRs) and 95% CIs were calculated by Cox proportional-hazards models and adjusted for vascular risk factors (age, sex, history of coronary disease, hypertension, diabetes, cholesterol, and smoking), stroke severity, infarct size, and stroke etiology.
The study population consisted of 655 patients whose mean age was 69.7 ± 12.7 years; 44.6% were men and 51.3% were Hispanic. During a median follow-up of 4.0 years, 44 patients (6.7%) had fatal cardiac events. Of these, fatal MI occurred in 38.6%, fatal congestive heart failure in 18.2%, and sudden death in 43.2%. In multivariate models, clinical diagnosis of left parietal lobe infarction was associated with cardiac death (adjusted HR = 4.45; 95% CI, 1.83 to 10.83) and cardiac death or MI (adjusted HR = 3.30; 95% CI, 1.45 to 7.51). When analysis of anatomic location was restricted to neuroimaging (computed tomography, magnetic resonance imaging, or both [n = 447]), left parietal lobe infarction was associated with cardiac death (adjusted HR = 3.37; 95% CI, 1.26 to 8.97), and both left (adjusted HR = 3.49; 95% CI, 1.38 to 8.80) and right (adjusted HR = 3.13; 95% CI, 1.04 to 9.45) parietal lobe infarctions were associated with cardiac death or MI. We did not find an association between frontal, temporal, or insular stroke and fatal cardiac events, although the number of purely insular strokes was small.
Parietal lobe infarction is an independent predictor of long-term cardiac death or MI in this population. Further studies are needed to confirm whether parietal lobe infarction is an independent predictor of cardiac events and death. Surveillance for cardiac disease and implementation of cardioprotective therapies may reduce cardiac mortality in patients with parietal stroke.
PMCID: PMC4112463  PMID: 18635863
acute stroke; cardiac arrhythmia; epidemiology; sudden death
14.  Patent Foramen Ovale, Subclinical Cerebrovascular Disease and Ischemic Stroke in a Population-Based Cohort 
To evaluate the relationship between patent foramen ovale (PFO), ischemic stroke and subclinical cerebrovascular disease in the general population.
PFO is more frequently found in stroke patients than in stroke-free controls. However, the PFO-related stroke risk in the general population is not well established, and the relationship between PFO and silent brain infarcts (SBI) is not known.
PFO presence was assessed by transthoracic echocardiography with saline contrast injection in 1,100 stroke-free individuals over age 39 of a community-based sample followed for a mean of 11 years. In addition, 360 participants underwent brain magnetic resonance imaging (MRI) for SBI detection. We evaluated the risk of stroke associated with PFO after adjusting for established stroke risk factors, and examined the odds of having SBI among those with and without PFO.
A PFO was present in 164 participants (14.9%). Over a mean follow up of 11.0 ± 4.5 years, 111 ischemic strokes occurred (10.1%), 15 (9.2%) in the PFO + and 96 (10.3%) in the PFO− groups. The 12.5 year cumulative risk of stroke was 10.1% (standard error 2.5%) in the PFO+ and 10.4% (standard error 1.1%) in the PFO− group (p=0.46). The adjusted hazard ratio for PFO and stroke was 1.10 (95% confidence interval 0.64–1.91). In the MRI subcohort, PFO was not associated with SBI (adjusted odds ratio 1.15, 95% CI 0.50–2.62).
In this community-based cohort, PFO was not associated with an increased risk of clinical stroke or subclinical cerebrovascular disease.
PMCID: PMC3696432  PMID: 23644084
Echocardiography; Cerebrovascular Disorders; Atrium; Stroke; Epidemiology
15.  Preoperative Serum Albumin Levels Predict 1-Year Postoperative Survival of Patients Undergoing Heart Transplantation 
Circulation. Heart failure  2013;6(4):785-791.
Serum albumin concentration has been recognized as a marker of nutrition, severity of inflammation, and hepatic function in patients with various chronic diseases. The purpose of this study was to investigate the impact of pretransplant serum albumin concentration on post-transplant outcome in heart transplant recipients.
Methods and Results
Preoperative laboratory variables, including albumin concentration and donor-related information, were obtained from 822 consecutive patients undergoing heart transplant at Columbia University Medical Center between 1999 and 2010. The association between pretransplant albumin concentration and post-transplant 1-year survival was analyzed. Available data from the United Network for Organ Sharing (n=13 671) were also analyzed to evaluate the impact of preoperative albumin levels on post-transplant outcome. In our cohort, multivariable analysis revealed that preoperative albumin (mg/dL; hazard ratio, 0.46; P<0.0001) and preoperative total bilirubin (mg/dL; hazard ratio, 1.26; P=0.0002) were associated with post-transplant 1-year mortality. This implied that for every 1 mg/dL increase in albumin concentration, the post-transplant 1-year mortality rate decreased by 54%. The Kaplan–Meier analysis based on our patients cohort and the United Network for Organ Sharing dataset showed lower survival rate at 1-year post-transplant in patients with albumin levels ≤3.5 mg/dL compared with those with >3.5 mg/dL (our patients, 91.3 versus 72.4%; P<0.0001; United Network for Organ Sharing, 88.4 versus 84.8%; P<0.0001).
Pretransplant serum albumin concentration is a strong prognostic marker for post-transplant survival in heart transplant recipients.
PMCID: PMC4074373  PMID: 23674361
albumin; heart transplantation; prognosis
16.  The Risk of Paradoxical Embolism (RoPE) Study: Initial description of the completed database 
Detecting a benefit from closure of patent foramen ovale (PFO) in patients with cryptogenic stroke (CS) is hampered by low rates of stroke recurrence and uncertainty about the causal role of PFO in the index event. A method to predict PFO-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence.
To develop a database to support modeling of PFO-attributable recurrence risk by combining extant data sets.
We identified investigators with extant databases including subjects with CS investigated for PFO; determined the availability and characteristics of data in each database; collaboratively specified the variables to be included in the Risk of Paradoxical Embolism (RoPE) database; harmonized the variables across databases, and collected new primary data when necessary and feasible.
The RoPE database has individual clinical, radiologic, and echocardiographic data from 12 component databases including subjects with CS both with (n=1925) and without (n=1749) PFO. In the PFO subjects, a total of 381 outcomes (stroke, TIA, death) occurred (median follow-up = 2.2yrs). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling.
While individual studies are inadequate for modeling PFO-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a PFO-related stroke recurrence who may have the greatest potential benefit from PFO closure.
PMCID: PMC4060865  PMID: 22883936
cryptogenic stroke; patent foramen ovale; secondary stroke prevention; risk modeling; endovascular closure; individual patient metaanalysis
17.  Serial Echocardiography Using Tissue Doppler and Speckle Tracking Imaging to Monitor Right Ventricular Failure Before and After Left Ventricular Assist Device Surgery 
JACC. Heart failure  2013;1(3):216-222.
This study aimed to investigate the utility of serial tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) for monitoring right ventricular failure (RVF) after left ventricular assist device (LVAD) surgery.
RVF post-LVAD is a devastating adverse event.
The authors prospectively studied 68 patients undergoing elective LVAD surgery. Echocardiograms were performed within 72 h before and 72 h after surgery. RVF was pre-specified as: 1) the need for salvage right ventricular assist device (RVAD); or 2) persistent need for inotrope and/or pulmonary vasodilator therapy 14 days after surgery. Patients were classified as Group RVF or Group Non-RVF.
A total of 24 patients (35.3%) met criteria for RVF. Preoperative TDI-derived S’ was lower and RV E/E’ ratio was higher (3.7 ± 0.6 cm/s vs. 4.7 ± 0.9 cm/s, 12.0 ± 2.3 vs. 10.0 ± 2.5, both p < 0.001, respectively), and the absolute value of RV longitudinal strain (RV-strain) obtained from STE was lower (−12.6 ± 3.3% vs. −16.2 ± 4.3%, p < 0.001) in Group RVF vs. Group Non-RVF. Echo parameters within 72 h after surgery showed higher RV-E/E’, (13.9 ± 4.6 vs. 10.1 ± 3.0, p < 0.001) and lower RV-strain (−11.8 ± 3.5% vs. −16.7 ± 4.4%, p < 0.001) in Group RVF vs. Group Non-RVF. Preoperative S’ <4.4 cm/s, RV-E/E’>10 and RV-strain < −14% discriminated patients who developed RVF at day 14 with a predictive accuracy of 76.5%. When we included postoperative RV-E/E’ and RV-strain, the predictive accuracy increased to 80.9%, with a sensitivity of 66.7% and a specificity of 88.7%.
Serial echocardiograms using TDI and STE before and soon after LVAD surgery may aid in identifying need to initiate targeted RVF specific therapy in this population.
PMCID: PMC3997790  PMID: 24621873
echocardiogram; heart failure; left ventricular assist device; prediction; right ventricular failure
18.  Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels 
In humans, obesity is associated with long QT, increased frequency of premature ventricular complexes, and sudden cardiac death. The mechanisms of the pro-arrhythmic electrophysiologic remodeling of obesity are poorly understood. We tested the hypothesis that there is decreased expression of voltage-gated potassium channels in the obese heart, leading to long QT. Using implanted telemeters, we found that diet-induced obese (DIO) wild-type mice have impaired cardiac repolarization, demonstrated by long QT, as well as more frequent ventricular ectopy, similar to obese humans. DIO mice have reduced protein and mRNA levels of the potassium channel Kv1.5 caused by a reduction of the transcription factor cyclic AMP response element binding protein (CREB) in DIO hearts. We found that CREB knock-down by siRNA reduces Kv1.5, CREB binds to the Kv1.5 promoter in the heart, and CREB increases transcription of mouse and human Kv1.5 promoters. The reduction in CREB protein during lipotoxicity can be rescued by inhibiting protein kinase D (PKD). Our results identify a mechanism for obesity-induced electrophysiologic remodeling in the heart, namely PKD-induced reduction of CREB, which in turn decreases expression of the potassium channel Kv1.5.
PMCID: PMC3647001  PMID: 23517696
obesity; arrhythmia; cyclic AMP response element binding protein; Kv1.5; protein kinase D
19.  Chronic Ethanol Consumption Increases Cardiomyocyte Fatty Acid Uptake and Decreases Ventricular Contractile Function in C57BL/6J Mice 
Alcohol, a major cause of human cardiomyopathy, decreases cardiac contractility in both animals and man. However, key features of alcohol-related human heart disease are not consistently reproduced in animal models. Accordingly, we studied cardiac histology, contractile function, cardiomyocyte long chain fatty acid (LCFA) uptake, and gene expression in male C57BL/6J mice consuming 0, 10, 14, or 18% ethanol in drinking water for 3 months. At sacrifice, all EtOH groups had mildly decreased body and increased heart weights, dose-dependent increases in cardiac triglycerides and a marked increase in cardiac fatty acid ethyl esters. [3H]-oleic acid uptake kinetics demonstrated increased facilitated cardiomyocyte LCFA uptake, associated with increased expression of genes encoding the LCFA transporters CD36 and Slc27a1 (FATP1) in EtOH-fed animals. Although SCD-1 expression was increased, lipidomic analysis did not indicate significantly increased de novo LCFA synthesis. By echocardiography, ejection fraction (EF) and the related fractional shortening (FS) of left ventricular diameter during systole were reduced and negatively correlated with cardiac triglycerides. Expression of myocardial PGC-1α and multiple downstream target genes in the oxidative phosphorylation pathway, including several in the electron transport and ATP synthase complexes of the inner mitochondrial membrane, were down-regulated. Cardiac ATP was correspondingly reduced. The data suggest that decreased expression of PGC-1α and its target genes result in decreased cardiac ATP levels, which may explain the decrease in myocardial contractile function caused by chronic EtOH intake. This model recapitulates important features of human alcoholic cardiomyopathy and illustrates a potentially important pathophysiologic link between cardiac lipid metabolism and function.
PMCID: PMC3647020  PMID: 23422163
ethanol consumption; lipid accumulation; fatty acid transport; PGC-1α; cardiac function; ATP; gene expression
20.  Alterations in Diastolic Function in Masked Hypertension: Findings from the Masked Hypertension Study 
American Journal of Hypertension  2013;26(6):808-815.
In a prior study of patients with diabetes, diastolic function was similarly impaired in masked hypertension (MHT) and sustained hypertension (SHT). We evaluated whether MHT is associated with impaired diastolic function compared with SHT and sustained normotension (NT) in the general population.
From February 2005 to December 2010, 798 participants without a history of cardiovascular disease or treated hypertension, were enrolled in the Masked Hypertension Study. Participants underwent clinic blood pressure (CBP) and 24-hour ambulatory blood pressure (ABP) measurements. A 2-dimensional Doppler echocardiogram was performed to evaluate diastolic function,s cardiac structure, volume, and systolic function. The 9 CBPs obtained across 3 clinic visits and awake ABP measurements were averaged. Clinic hypertension was defined as systolic/diastolic blood pressure (SBP/DBP) ≥ 140/90 mmHg. Ambulatory hypertension was defined as awake SBP/DBP ≥ 135/85mm Hg. MHT was defined as having ambulatory but not clinic hypertension. White-coat hypertensives (n = 8) were excluded from the analysis.
Of the 790 participants, 116 (14.7%) participants had MHT, 37 (4.7%) participants had SHT, and 637 (80.6%) participants had NT. After age, sex, race/ethnicity, and body mass index adjustment, compared with NT, E’-velocities were significantly lower in MHT (P < 0.01) and SHT (P < 0.05), and E/E’ ratios were significantly higher MHT (P < 0.05) and SHT (P < 0.05). These associations were independent of left ventricular mass. Diastolic function parameters did not significantly differ between MHT and SHT.
Diastolic function was impaired in MHT compared with NT independent of changes in left ventricular mass.
PMCID: PMC3657486  PMID: 23446956
ambulatory blood pressure monitoring; blood pressure;  echocardiography; hypertension.
21.  Socioeconomic Status, Psychosocial Factors, Race and Nocturnal Blood Pressure Dipping in a Hispanic Cohort 
American Journal of Hypertension  2013;26(5):673-682.
Little information is available about the relationship of socioeconomic status (SES) to blunted nocturnal ambulatory blood pressure (ABP) dipping among Hispanics and whether this relationship differs by race. We sought to characterize ABP nondipping and its determinants in a sample of Hispanics.
We enrolled 180 Hispanic participants not on antihypertensive medications. SES was defined by years of educational attainment. All participants underwent 24-hour ABP monitoring. A decrease of <10% in the ratio between average awake and average asleep systolic BP was considered nondipping.
The mean age of the cohort was 67.1 ± 8.7, mean educational level was 9.4 ± 4.4 years, and 58.9% of the cohort was female. The cohort was comprised of 78.3% Caribbean Hispanics with the rest from Mexico and Central/South America; 41.4% self-identified as white Hispanic, 34.4% self-identified as black Hispanic, and 24.4% did not racially self- identify. The percentage of nondippers was 57.8%. Educational attainment (10.5 years vs. 8.6 years; P <0.01) was significantly higher among dippers than nondippers. In multivariable analyses, each 1-year increase in education was associated with a 9% reduction in the likelihood of being a nondipper (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.84–0.98; P = 0.01). There were significantly greater odds of being a nondipper for black Hispanics than for white Hispanics (OR, 2.83, 95% CI, 1.29–6.23; P = 0.005). Higher SES was significantly protective of nondipping in white Hispanics but not black Hispanics.
These results document a substantial prevalence of nondipping in a cohort of predominantly normotensive Hispanics. Dipping status varied significantly by race. Lower SES is significantly associated with nondipping status, and race potentially impacts on this relation.
PMCID: PMC3657484  PMID: 23547037
ambulatory blood pressure monitoring; blood pressure; Hispanics; hypertension; psychosocial; race; socioeconomic status.
22.  PPARγ Activation Prevents Sepsis-Related Cardiac Dysfunction and Mortality in Mice 
Circulation. Heart failure  2013;6(3):550-562.
Cardiac dysfunction with sepsis is associated with both inflammation and reduced fatty acid oxidation (FAO). We hypothesized that energy deprivation accounts for sepsis-related cardiac dysfunction.
Methods and Results
E. coli lipopolysaccharide (LPS) administered to C57BL/6 mice (WT) induced cardiac dysfunction and reduced FAO and mRNA levels of peroxisome proliferator-activated receptor (PPAR) α and its downstream targets within 6-8h. Transgenic mice in which cardiomyocyte-specific expression of PPARγ is driven by the alpha myosin heavy chain promoter (αMHC-PPARγ) were protected from LPS-induced cardiac dysfunction. Despite a reduction in PPARα, FAO and associated genes were not decreased in hearts of LPS-treated αMHC-PPARγ mice. LPS treatment, however, continued to induce inflammation-related genes, such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α in hearts of αMHC-PPARγ mice. Treatment of WT mice with LPS and the PPARγ agonist rosiglitazone, but not the PPARα agonist (WY-14643), increased FAO, prevented LPS-mediated reduction of mitochondria and treated cardiac dysfunction, as well as it improved survival despite continued increases in the expression of cardiac inflammatory markers.
Activation of PPARγ in LPS-treated mice prevented cardiac dysfunction and mortality despite development of cardiac inflammation and PPARα downregulation.
PMCID: PMC3690188  PMID: 23572494
fatty acids; sepsis; PPAR; cardiac metabolism
23.  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
24.  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
25.  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

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