A5075085526- Cardiac electrophysiology and arrhythmias
- Cardiomyopathy and Myosin Studies
- Ion channel regulation and function
- Cardiovascular Function and Risk Factors
- Viral Infections and Immunology Research
- Cardiac Fibrosis and Remodeling
- Cardiovascular Effects of Exercise
- Signaling Pathways in Disease
- CRISPR and Genetic Engineering
- Congenital heart defects research
- Virus-based gene therapy research
- Alzheimer's disease research and treatments
- Cardiac Ischemia and Reperfusion
- Endoplasmic Reticulum Stress and Disease
- Cardiac Structural Anomalies and Repair
- Receptor Mechanisms and Signaling
- Neuroscience and Neural Engineering
- Tissue Engineering and Regenerative Medicine
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Viral Infectious Diseases and Gene Expression in Insects
- Heat shock proteins research
- Pluripotent Stem Cells Research
- Peptidase Inhibition and Analysis
- RNA modifications and cancer
- Adipose Tissue and Metabolism
Medical University of South Carolina
2017-2025
University of Bologna
2020-2025
Massachusetts General Hospital
2004-2023
Harvard University
2004-2023
Mass General Brigham
2023
Imperial College London
1996-2016
Beth Israel Deaconess Medical Center
2005-2016
Deaconess Hospital
2016
Beth Israel Deaconess Hospital
2010-2016
King's College London
2016
The serine-threonine kinase Akt is activated by several ligand-receptor systems previously shown to be cardioprotective. activation reduces cardiomyocyte apoptosis in models of transient ischemia. Its role cardiac dysfunction or infarction, however, remains unclear.We examined the effects a constitutively active mutant (myr-Akt) rat model ischemia-reperfusion injury. In vivo gene transfer myr-Akt reduced infarct size 64% and number apoptotic cells 84% (P<0.005 for each). Ischemia-reperfusion...
In human and experimental models of heart failure, sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling. The disturbances metabolism have been shown to contribute significantly the contractile dysfunction observed failure. We investigated whether increasing SERCA2a expression can improve ventricular function an animal model failure obtained by creating ascending aortic constriction rats. After 19–23 wk banding during transition from...
Background —Failing human myocardium is characterized by abnormal relaxation, a deficient sarcoplasmic reticulum (SR) Ca 2+ uptake, and negative frequency response, which have all been related to deficiency in the SR ATPase (SERCA2a) pump. Methods Results —To test hypothesis that an increase SERCA2a could improve contractile function cardiomyocytes, we overexpressed ventricular myocytes from 10 patients with end-stage heart failure examined intracellular handling function. Overexpression of...
Background —Left ventricular failure is commonly preceded by a period of hypertrophy. Intriguingly, many the signaling pathways that have been implicated in regulation hypertrophy, including 3 mitogen-activated protein kinases (MAPKs: extracellular signal-regulated kinase, stress-activated and p38), phosphatase, calcineurin, kinase Akt its target glycogen synthase kinase-3 (GSK-3), also regulate apoptotic response. Methods Results —To understand mechanisms might progression heart failure, we...
RETRACTION This article has been retracted: Circ Res . 2018;123:e00. DOI: 10.1161/RES.0000000000000246
Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy a median survival of less than 8 months and 5-year <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying deadly form disease remain unclear. Although interstitial amyloid fibril deposition Ig light chain proteins major cause dysfunction in AL amyloidosis, we have previously shown precursor...
RETRACTION This article has been retracted: Circ Res . 2018;123:e00. DOI: 10.1161/RES.0000000000000247
Background —The intracellular signaling pathways that control cardiomyocyte apoptosis have not been fully defined. Because insulin-like growth factor-1 (IGF-1) prevents apoptosis, we examined the role of its downstream molecules in an vitro model hypoxia-induced apoptosis. Methods and Results —Treatment rat neonatal cardiomyocytes with IGF-1 increased activity both phosphatidylinositol 3′ (PI 3)-kinase target, Akt (also known as protein kinase B or PKB). Cardiomyocytes were subjected to...
Background — In heart failure, sarcoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling and contractile dysfunction. We have previously shown that increasing SERCA2a expression by gene transfer improves ventricular function a rat model of failure created ascending aortic constriction. Methods Results this study, we tested the effects on survival, left (LV) volumes, metabolism. By 26 to 27 weeks after banding, all animals developed (as...
Background— Ischemia-induced cardiomyopathy usually is accompanied by elevated left ventricular end-diastolic pressure, which follows from increased myocardial stiffness resulting upregulated collagen expression. In addition to collagen, a main determinant of titin, whose role in ischemia-induced stiffening was studied here. Human heart sarcomeres coexpress 2 principal titin isoforms, more compliant N2BA isoform and stiffer N2B isoform. comparison, normal rat hearts express almost no titin....
In the pathogenesis of dilated cardiomyopathy, cytoskeletal proteins play an important role. this study, we analyzed titin expression in left ventricles 19 control human donors and 9 severely diseased (nonischemic) cardiomyopathy (DCM) transplant-patients, using gel-electrophoresis, immunoblotting, quantitative RT-PCR. Both human-heart groups coexpressed smaller (approximately 3 MDa) N2B-isoform longer (3.20 to 3.35 N2BA-isoforms, but average N2BA:N2B-protein ratio was shifted from...
Background — Myocardial cells from failing human hearts are characterized by abnormal calcium handling, a negative force-frequency relationship, and decreased sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) activity. In this study, we tested whether contractile function can be improved decreasing the inhibitory effects of phospholamban on SERCA2a with adenoviral gene transfer antisense (asPL). Methods Results isolated 9 patients end-stage heart failure 18 donor nonfailing were infected...
Increases in type 1 phosphatase (PP1) activity have been observed end stage human heart failure, but the role of this enzyme cardiac function is unknown.To elucidate functional significance increased PP1 activity, we generated models with (i) overexpression catalytic subunit murine hearts and (ii) ablation PP1-specific inhibitor.Overexpression (threefold) was associated depressed function, dilated cardiomyopathy, premature mortality, consistent failure.Ablation inhibitor moderate increases...
Acute activation of the serine-threonine kinase Akt is cardioprotective and reduces both infarction dysfunction after ischemia/reperfusion injury (IRI). However, less known about chronic effects in heart, and, paradoxically, activated samples from patients with heart failure. We generated Tg mice cardiac-specific expression either (myristoylated [myr]) or dominant-negative (dn) assessed their response to IRI an ex vivo model. While dn-Akt hearts demonstrated a moderate reduction functional...
Rationale : Mitochondrial dysfunction plays a pivotal role in the development of heart failure. Animal studies suggest that impaired mitochondrial biogenesis attributable to downregulation peroxisome proliferator-activated receptor γ coactivator (PGC)-1 transcriptional pathway is integral Objective The study sought define mechanisms underlying and function human Methods Results We collected left ventricular tissue from end-stage failure patients nonfailing hearts (n=23, 19, respectively)....
Abnormal calcium cycling, characteristic of experimental and human heart failure, is associated with impaired sarcoplasmic reticulum uptake activity. This reflects decreases in the cAMP-pathway signaling increases type 1 phosphatase The increased protein activity partially due to dephosphorylation inactivation its inhibitor-1, promoting phospholamban inhibition calcium-pump. Indeed, cardiac-specific expression a constitutively active inhibitor-1 results selective enhancement phosphorylation...
Abnormal intracellular Ca 2+ cycling plays an important role in cardiac dysfunction and ventricular arrhythmias the setting of heart failure transient ischemia followed by reperfusion (I/R). We hypothesized that overexpression sarcoplasmic reticulum ATPase pump (SERCA2a) may improve both contractile arrhythmias. Continuous ECG recordings were obtained 46 conscious rats after adenoviral gene transfer either SERCA2a or reporter β-galactosidase (βgal) parvalbumin (PV), as early 48 h before 30...
The Ca 2+ -calmodulin-activated Ser/Thr protein phosphatase calcineurin and the downstream transcriptional effectors of calcineurin, nuclear factor activated T cells, have been implicated in hypertrophic response myocardium. Recently, inhibitory agents cyclosporine A FK506 extensively used to evaluate importance this signaling pathway rodent models cardiac hypertrophy. However, pharmacologic approaches rendered equivocal results necessitating more specific or genetic-based strategies. In...
RETRACTION This article has been retracted: Circulation . 2019;139:e1. DOI: 10.1161/CIR.0000000000000644
Genetic variants on chromosome 4q25 are associated with atrial fibrillation (AF). We sought to determine whether there is more than 1 susceptibility signal at this locus.Thirty-four haplotype-tagging single-nucleotide polymorphisms (SNPs) the locus were genotyped in 790 case and 1177 control subjects from Massachusetts General Hospital tested for association AF. replicated SNPs AF after adjustment most significantly SNP 5066 30 661 referent German Competence Network Atrial Fibrillation,...