Section of Cardiovascular Medicine

Head of Westport, MA, United States

Section of Cardiovascular Medicine

Head of Westport, MA, United States
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Ren B.,Cleveland Clinic | Deng Y.,Section of Cardiovascular Medicine | Mukhopadhyay A.,Harvard University | Lanahan A.A.,Section of Cardiovascular Medicine | And 5 more authors.
Journal of Clinical Investigation | Year: 2010

Arterial morphogenesis is an important and poorly understood process. In particular, the signaling events controlling arterial formation have not been established. We evaluated whether alterations in the balance between ERK1/2 and PI3K signaling pathways could stimulate arterial formation in the setting of defective arterial morphogenesis in mice and zebrafish. Increased ERK1/2 activity in mouse ECs with reduced VEGF responsiveness was achieved in vitro and in vivo by downregulating PI3K activity, suppressing Akt1 but not Akt2 expression, or introducing a constitutively active ERK1/2 construct. Such restoration of ERK1/2 activation was sufficient to restore impaired arterial development and branching morphogenesis in synectin-deficient mice and synectin-knockdown zebrafish. The same approach effectively stimulated arterial growth in adult mice, restoring arteriogenesis in mice lacking synectin and in atherosclerotic mice lacking both LDL-R and ApoB48. We therefore conclude that PI3K-ERK1/2 crosstalk plays a key role in the regulation of arterial growth and that the augmentation of ERK signaling via suppression of the PI3K signaling pathway can effectively stimulate arteriogenesis.


Xu X.,Gynecology and Reproductive science | Xu X.,Yale New Haven Hospital | Bao H.,Yale New Haven Hospital | Strait K.,Yale New Haven Hospital | And 12 more authors.
Circulation | Year: 2015

Background-Younger age and female sex are both associated with greater mental stress in the general population, but limited data exist on the status of perceived stress in young and middle-aged patients presenting with acute myocardial infarction. Methods and Results-We examined sex difference in stress, contributing factors to this difference, and whether this difference helps explain sex-based disparities in 1-month recovery using data from 3572 patients with acute myocardial infarction (2397 women and 1175 men) 18 to 55 years of age. The average score of the 14-item Perceived Stress Scale at baseline was 23.4 for men and 27.0 for women (P<0.001). Higher stress in women was explained largely by sex differences in comorbidities, physical and mental health status, intrafamily conflict, caregiving demands, and financial hardship. After adjustment for demographic and clinical characteristics, women had worse recovery than men at 1 month after acute myocardial infarction, with mean differences in improvement score between women and men ranging from -0.04 for EuroQol utility index to -3.96 for angina-related quality of life (P<0.05 for all). Further adjustment for baseline stress reduced these sex-based differences in recovery to -0.03 to -3.63, which, however, remained statistically significant (P<0.05 for all). High stress at baseline was associated with significantly worse recovery in angina-specific and overall quality of life, as well as mental health status. The effect of baseline stress on recovery did not vary between men and women. Conclusions-Among young and middle-aged patients, higher stress at baseline is associated with worse recovery in multiple health outcomes after acute myocardial infarction. Women perceive greater psychological stress than men at baseline, which partially explains women's worse recovery.


Jane-Wit D.,Section of Cardiovascular Medicine | Moeckel G.,Yale University | Pober J.S.,Yale University
Circulation | Year: 2013

BACKGROUND-: Cardiac allograft vasculopathy is the major cause of late allograft loss after heart transplantation. Cardiac allograft vasculopathy lesions contain alloreactive T cells that secrete interferon-γ, a vasculopathic cytokine, and occur more frequently in patients with donor-specific antibody. Pathological interactions between these immune effectors, representing cellular and humoral immunity, respectively, remain largely unexplored. METHODS AND RESULTS-: We used human panel reactive antibody to form membrane attack complexes on allogeneic endothelial cells in vitro and in vivo. Rather than inducing cytolysis, membrane attack complexes upregulated inflammatory genes, enhancing the capacity of endothelial cells to recruit and activate allogeneic interferon-γ-producing CD4 T cells in a manner dependent on the activation of noncanonical nuclear factor-κB signaling. Noncanonical nuclear factor-κB signaling was detected in situ within endothelial cells both in renal biopsies from transplantation patients with chronic antibody-mediated rejection and in panel-reactive antibody-treated human coronary artery xenografts in immunodeficient mice. On retransplantation into immunodeficient hosts engrafted with human T cells, panel-reactive antibody-treated grafts recruited more interferon-γ-producing T cells and enhanced cardiac allograft vasculopathy lesion formation. CONCLUSIONS-: Alloantibody and complement deposition on graft endothelial cells activates noncanonical nuclear factor-κB signaling, initiating a proinflammatory gene program that enhances alloreactive T cell activation and development of cardiac allograft vasculopathy. Noncanonical nuclear factor-κB signaling in endothelial cells, observed in human allograft specimens and implicated in lesion pathogenesis, may represent a target for new pharmacotherapies to halt the progression of cardiac allograft vasculopathy. © 2013 American Heart Association, Inc.


Krumholz H.M.,Section of Cardiovascular Medicine | Krumholz H.M.,Yale University | Krumholz H.M.,Yale New Haven Hospital | Krumholz H.M.,Section of Health Policy and Administration | And 16 more authors.
Circulation | Year: 2011

Background-: Registry studies have suggested improvements in door-to-balloon times, but a national assessment of the trends in door-to-balloon times is lacking. Moreover, we do not know whether improvements in door-to-balloon times were shared equally among patient and hospital groups. Methods and results-: This analysis includes all patients reported by hospitals to the Centers for Medicare & Medicaid Services for inclusion in the time to percutaneous coronary intervention (acute myocardial infarction-8) inpatient measure from January 1, 2005, through September 30, 2010. For each calendar year, we summarized the characteristics of patients reported for the measure, including the number and percentage in each group, the median time to primary percutaneous coronary intervention, and the percentage with time to primary percutaneous coronary intervention within 75 minutes and within 90 minutes. Door-to-balloon time declined from a median of 96 minutes in the year ending December 31, 2005, to a median of 64 minutes in the 3 quarters ending September 30, 2010. There were corresponding increases in the percentage of patients who had times <90 minutes (44.2% to 91.4%) and <75 minutes (27.3% to 70.4%). The declines in median times were greatest among groups that had the highest median times during the first period: patients >75 years of age (median decline, 38 minutes), women (35 minutes), and blacks (42 minutes). CONCLUSION-: National progress has been achieved in the timeliness of treatment of patients with ST-segment-elevation myocardial infarction who undergo primary percutaneous coronary intervention. © 2011 American Heart Association, Inc.


Al-Damluji M.S.,Section of General Internal Medicine | Dzara K.,Section of General Internal Medicine | Hodshon B.,Section of Cardiovascular Medicine | Punnanithinont N.,Erie County Medical Center | And 6 more authors.
Circulation: Cardiovascular Quality and Outcomes | Year: 2015

Background: Single-site studies have demonstrated inadequate quality of discharge summaries in timeliness, transmission, and content, potentially contributing to adverse outcomes. However, degree of hospital-level variation in discharge summary quality for patients hospitalized with heart failure (HF) is uncertain. Methods and Results: We analyzed discharge summaries of patients enrolled in the Telemonitoring to Improve Heart Failure Outcomes (Tele-HF) study. We assessed hospital-level performance on timeliness (fraction of summaries completed on the day of discharge), documented transmission to the follow-up physician, and content (presence of components suggested by the Transitions of Care Consensus Conference). We obtained 1501 discharge summaries from 1640 (91.5%) patients discharged alive from 46 hospitals. Among hospitals contributing ≥10 summaries, the median hospital dictated 69.2% of discharge summaries on the day of discharge (range, 0.0%-98.0%; P<0.001); documented transmission of 33.3% of summaries to the follow-up physician (range, 0.0%-75.7%; P<0.001); and included 3.6 of 7 Transitions of Care Consensus Conference elements (range, 2.9-4.5; P<0.001). Hospital course was typically included (97.2%), but summaries were less likely to include discharge condition (30.7%), discharge volume status (16.0%), or discharge weight (15.7%). No discharge summary included all 7 Transitions of Care Consensus Conference-endorsed content elements, was dictated on the day of discharge, and was sent to a follow-up physician. Conclusions: Even at the highest performing hospital, discharge summary quality is insufficient in terms of timeliness, transmission, and content. Improvements in all aspects of discharge summary quality are necessary to enable the discharge summary to serve as an effective transitional care tool. © 2015 American Heart Association, Inc.


Krumholz H.M.,Section of Cardiovascular Medicine | Krumholz H.M.,Yale University | Krumholz H.M.,Yale New Haven Hospital | Lin Z.,Yale New Haven Hospital | And 8 more authors.
Circulation: Cardiovascular Quality and Outcomes | Year: 2011

Background-National attention has increasingly focused on readmission as a target for quality improvement. We present the development and validation of a model approved by the National Quality Forum and used by the Centers for Medicare & Medicaid Services for hospital-level public reporting of risk-standardized readmission rates for patients discharged from the hospital after an acute myocardial infarction. Methods and Results-We developed a hierarchical logistic regression model to calculate hospital risk-standardized 30-day all-cause readmission rates for patients hospitalized with acute myocardial infarction. The model was derived using Medicare claims data for a 2006 cohort and validated using claims and medical record data. The unadjusted readmission rate was 18.9%. The final model included 31 variables and had discrimination ranging from 8% observed 30-day readmission rate in the lowest predictive decile to 32% in the highest decile and a C statistic of 0.63. The 25th and 75th percentiles of the risk-standardized readmission rates across 3890 hospitals were 18.6% and 19.1%, with fifth and 95th percentiles of 18.0% and 19.9%, respectively. The odds of all-cause readmission for a hospital 1 SD above average were 1.35 times that of a hospital 1 SD below average. Hospital-level adjusted readmission rates developed using the claims model were similar to rates produced for the same cohort using a medical record model (correlation, 0.98; median difference, 0.02 percentage points). Conclusions-This claims-based model of hospital risk-standardized readmission rates for patients with acute myocardial infarction produces estimates that are excellent surrogates for those produced from a medical record model. (Circ Cardiovasc Qual Outcomes. 2011;4:243-252.) © 2011 American Heart Association, Inc.


Girotra S.,University of Iowa | Nallamothu B.K.,University of Michigan | Spertus J.A.,Saint Lukes Mid America Heart Institute | Spertus J.A.,University of Missouri - Kansas City | And 6 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Despite advances in resuscitation care in recent years, it is not clear whether survival and neurologic function after in-hospital cardiac arrest have improved over time. METHODS: We identified all adults who had an in-hospital cardiac arrest at 374 hospitals in the Get with the Guidelines-Resuscitation registry between 2000 and 2009. Using multi-variable regression, we examined temporal trends in risk-adjusted rates of survival to discharge. Additional analyses explored whether trends were due to improved survival during acute resuscitation or postresuscitation care and whether they occurred at the expense of greater neurologic disability in survivors. RESULTS: Among 84,625 hospitalized patients with cardiac arrest, 79.3% had an initial rhythm of asystole or pulseless electrical activity, and 20.7% had ventricular fibrillation or pulseless ventricular tachycardia. The proportion of cardiac arrests due to asystole or pulseless electrical activity increased over time (P<0.001 for trend). Risk-adjusted rates of survival to discharge increased from 13.7% in 2000 to 22.3% in 2009 (adjusted rate ratio per year, 1.04; 95% confidence interval [CI], 1.03 to 1.06; P<0.001 for trend). Survival improvement was similar in the two rhythm groups and was due to improvement in both acute resuscitation survival and postresuscitation survival. Rates of clinically significant neurologic disability among survivors decreased over time, with a risk-adjusted rate of 32.9% in 2000 and 28.1% in 2009 (adjusted rate ratio per year, 0.98; 95% CI, 0.97 to 1.00; P = 0.02 for trend). CONCLUSIONS: Both survival and neurologic outcomes after in-hospital cardiac arrest have improved during the past decade at hospitals participating in a large national quality-improvement registry. (Funded by the American Heart Association.) Copyright © 2012 Massachusetts Medical Society.


Dash B.C.,Section of Cardiovascular Medicine | Dash B.C.,Yale University | Jiang Z.,Section of Cardiovascular Medicine | Jiang Z.,Yale University | And 4 more authors.
Biochemical Journal | Year: 2015

Vascular smooth muscle cells (VSMCs) play a major role in the pathophysiology of cardiovascular diseases. The advent of induced pluripotent stem cell (iPSC) technology and the capability of differentiating into virtually every cell type in the human body make this field a ray of hope for vascular regenerative therapy and understanding of the disease mechanism. In the present review, we first discuss the recent iPSC technology and vascular smooth muscle development from an embryo and then examine different methodologies to derive VSMCs from iPSCs, and their applications in regenerative therapy and disease modelling. © The Authors Journal compilation. © 2015 Biochemical Society.


Song Y.,Section of Cardiovascular Medicine | Song Y.,Yale University | Shen H.,Section of Cardiovascular Medicine | Shen H.,Yale University | And 5 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

Objective-: Increased circulating cytokine levels are a prominent feature of aging that may contribute to atherosclerosis. However, the role vascular cells play in chronic inflammation induced by aging is not clear. Here, we examined the role of aging on inflammatory responses of vascular cells. Methods and Results-: In an ex vivo culture system, we examined the inflammatory response of aortas from young (2-4 months) and aged (16-18 months) mice under nonstimulatory conditions. We found that basal levels of interleukin-6 were increased in aged aortas. Aged aortic vascular smooth muscle cells (VSMC) exhibited a higher basal secretion of interleukin-6 than young VSMC. Gene and protein expression analysis revealed that aged VSMC exhibited upregulation of chemokines (eg, CCL2), adhesion molecules (eg, intracellular adhesion molecule 1), and innate immune receptors (eg, Toll-like receptor [TLR] 4), which all contribute to atherosclerosis. Using VSMC from aged TL4 -/- and Myd88 -/- mice, we demonstrate that signaling via TLR4 and its signal adaptor, MyD88, are in part responsible for the age-elevated basal interleukin-6 response. Conclusion-: Aging induces a proinflammatory phenotype in VSMC due in part to increased signaling of TLR4 and MyD88. Our results provide a potential explanation as to why aging leads to chronic inflammation and enhanced atherosclerosis. © 2011 American Heart Association, Inc.


Gandhi P.U.,Section of Cardiovascular Medicine | Gandhi P.U.,Yale University | Testani J.M.,Yale University | Ahmad T.,Yale University
Current Heart Failure Reports | Year: 2015

Heart failure is a growing epidemic, and our understanding of the intricacies of its pathophysiology continues to evolve. Over the last decade, biomarkers of heart failure have been extensively investigated, particularly for diagnosis and risk stratification. While the natriuretic peptides remain the gold standard heart failure biomarker, they are plagued by their non-specific nature; furthermore, the strategy of natriuretic peptide-guided care remains elusive. Multiple candidate markers indicative of other physiologic aspects of heart failure have been identified and studied, including soluble ST2, galectin-3, and high-sensitivity cardiac troponins. Each of these biomarkers has the potential to provide unique therapeutically relevant information. Ultimately, a multi-marker approach may be applied to improve care of patients with heart failure. Definitive clinical trials and the use of advanced statistical analytic techniques are needed to truly determine the optimal strategy of biomarker-assisted diagnosis, prognostication, and management of patients who suffer from this devastating condition. © 2015, Springer Science+Business Media New York.

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