Browsing by Subject "Heart Ventricles"
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Item Open Access Aorta-to-pulmonary vein fistula in an asymptomatic 25-year-old man.(Circulation, 2013-04-23) Dahiya, Arun; Collier, Patrick; Krasuski, Richard; Kalahasti, Vidyasagar; Del Nido, Pedro; Stewart, William JItem Open Access Assessing cardiac injury in mice with dual energy-microCT, 4D-microCT, and microSPECT imaging after partial heart irradiation.(Int J Radiat Oncol Biol Phys, 2014-03-01) Lee, Chang-Lung; Min, Hooney; Befera, Nicholas; Clark, Darin; Qi, Yi; Das, Shiva; Johnson, G Allan; Badea, Cristian T; Kirsch, David GPURPOSE: To develop a mouse model of cardiac injury after partial heart irradiation (PHI) and to test whether dual energy (DE)-microCT and 4-dimensional (4D)-microCT can be used to assess cardiac injury after PHI to complement myocardial perfusion imaging using micro-single photon emission computed tomography (SPECT). METHODS AND MATERIALS: To study cardiac injury from tangent field irradiation in mice, we used a small-field biological irradiator to deliver a single dose of 12 Gy x-rays to approximately one-third of the left ventricle (LV) of Tie2Cre; p53(FL/+) and Tie2Cre; p53(FL/-) mice, where 1 or both alleles of p53 are deleted in endothelial cells. Four and 8 weeks after irradiation, mice were injected with gold and iodinated nanoparticle-based contrast agents, and imaged with DE-microCT and 4D-microCT to evaluate myocardial vascular permeability and cardiac function, respectively. Additionally, the same mice were imaged with microSPECT to assess myocardial perfusion. RESULTS: After PHI with tangent fields, DE-microCT scans showed a time-dependent increase in accumulation of gold nanoparticles (AuNp) in the myocardium of Tie2Cre; p53(FL/-) mice. In Tie2Cre; p53(FL/-) mice, extravasation of AuNp was observed within the irradiated LV, whereas in the myocardium of Tie2Cre; p53(FL/+) mice, AuNp were restricted to blood vessels. In addition, data from DE-microCT and microSPECT showed a linear correlation (R(2) = 0.97) between the fraction of the LV that accumulated AuNp and the fraction of LV with a perfusion defect. Furthermore, 4D-microCT scans demonstrated that PHI caused a markedly decreased ejection fraction, and higher end-diastolic and end-systolic volumes, to develop in Tie2Cre; p53(FL/-) mice, which were associated with compensatory cardiac hypertrophy of the heart that was not irradiated. CONCLUSIONS: Our results show that DE-microCT and 4D-microCT with nanoparticle-based contrast agents are novel imaging approaches complementary to microSPECT for noninvasive assessment of the change in myocardial vascular permeability and cardiac function of mice in whom myocardial injury develops after PHI.Item Open Access Associations between physical activity, sedentary behaviour and left ventricular structure and function from the Echocardiographic Study of Latinos (ECHO-SOL).(Open heart, 2021-07) Berdy, Andrew E; Upadhya, Bharathi; Ponce, Sonia; Swett, Katrina; Stacey, Richard B; Kaplan, Robert; Vasquez, Priscilla M; Qi, Qibin; Schneiderman, Neil; Hurwitz, Barry E; Daviglus, Martha L; Kansal, Mayank; Evenson, Kelly R; Rodriguez, Carlos JThe cross-sectional association between accelerometer-measured physical activity (PA), sedentary behaviour (SB) and cardiac structure and function is less well described. This study's primary aim was to compare echocardiographic measures of cardiac structure and function with accelerometer measured PA and SB. Participants included 1206 self-identified Hispanic/Latino men and women, age 45-74 years, from the Echocardiographic Study of Latinos. Standard echocardiographic measures included M-mode, two-dimensional, spectral, tissue Doppler and myocardial strain. Participants wore an Actical accelerometer at the hip for 1 week. The mean±SE age for the cohort was 56±0.4 years, 57% were women. Average moderate to vigorous PA (MVPA) was 21±1.1 min/day, light PA was 217±4.2 min/day and SB was 737±8.1 min/day. Both higher levels of light PA and MVPA (min/day) were associated with lower left ventricular (LV) mass index (LVMI)/end-diastolic volume and a lower E/e' ratio. Higher levels of MVPA (min/day) were associated with better right ventricular systolic function. Higher levels of SB were associated with increased LVMI. In a multivariable linear regression model adjusted for demographics and cardiovascular disease modifiable factors, every 10 additional min/day of light PA was associated with a 0.03 mL/m2 increase in left atrial volume index (LAVI) (p<0.01) and a 0.004 cm increase in tricuspid annular plane systolic excursion (p<0.01); every 10 additional min/day of MVPA was associated with a 0.18 mL/m2 increase in LAVI (p<0.01) and a 0.24% improvement in global circumferential strain (p<0.01). Our findings highlight the potential positive association between the MVPA and light PA on cardiac structure and function.Item Open Access Bbeta-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by beta- but not alpha1-adrenergic stimulation.(Hypertension, 1999-01) Dolber, Paul Christian; Iaccarino, Guido; Koch, Walter J; Lefkowitz, Robert JPressure overload ventricular hypertrophy is accompanied by dysfunctional beta-adrenergic receptor signaling due to increased levels of the beta-adrenergic receptor kinase-1, which phosphorylates and desensitizes beta-adrenergic receptors. In this study, we examined whether increased beta-adrenergic receptor kinase 1 expression is associated with myocardial hypertrophy induced by adrenergic stimulation. With use of implanted mini-osmotic pumps, we treated mice with isoproterenol, phenylephrine, or vehicle to distinguish between alpha1- and beta-adrenergic stimulation. Both treatments resulted in cardiac hypertrophy, but only isoproterenol induced significant increases in beta-adrenergic receptor kinase-1 protein levels and activity. Similarly, in isolated adult rat cardiac myocytes, 24 hours of isoproterenol stimulation resulted in a significant 2.8-fold increase in beta-adrenergic receptor kinase-1 protein levels, whereas 24 hours of phenylephrine treatment did not alter beta-adrenergic receptor kinase-1 expression. Our results indicate that increased beta-adrenergic receptor kinase-1 is not invariably associated with myocardial hypertrophy but apparently is controlled by the state of beta-adrenergic receptor activation.Item Open Access Cardiac injury due to accidental discharge of nail gun.(The Journal of emergency medicine, 2013-02) Temple, Alton D; Fesmire, Francis M; Seaberg, David C; Severance, Harry WBackground
Since 1991, the incidence of injuries associated with pneumatic and explosive powered nail guns has steadily been rising due to increasing use of these devices by the untrained consumer. The vast majority of injuries involve the extremities, but injuries have been reported to occur in virtually every area of the body.Objective
Discuss the epidemiology, pathophysiology, and management of penetrating cardiac nail gun injuries.Case report
A 33-year-old man sustained a penetrating cardiac injury from accidental discharge of a nail gun. The patient had successful repair of a laceration to his right ventricle.Conclusions
Penetrating cardiac injuries from pneumatic nail guns are rare and have mortality similar to stab wounds. Improved safety mechanisms and training are the keys to prevention. Consideration also should be given to implementing legislation restricting the sale of nail guns.Item Open Access Clinical and echocardiographic predictors of mortality in acute pulmonary embolism.(Cardiovasc Ultrasound, 2016-10-28) Dahhan, Talal; Siddiqui, Irfan; Tapson, Victor F; Velazquez, Eric J; Sun, Stephanie; Davenport, Clemontina A; Samad, Zainab; Rajagopal, SudarshanPURPOSE: The aim of this study was to evaluate the utility of adding quantitative assessments of cardiac function from echocardiography to clinical factors in predicting the outcome of patients with acute pulmonary embolism (PE). METHODS: Patients with a diagnosis of acute PE, based on a positive ventilation perfusion scan or computed tomography (CT) chest angiogram, were identified using the Duke University Hospital Database. Of these, 69 had echocardiograms within 24-48 h of the diagnosis that were suitable for offline analysis. Clinical features that were analyzed included age, gender, body mass index, vital signs and comorbidities. Echocardiographic parameters that were analyzed included left ventricular (LV) ejection fraction (EF), regional, free wall and global RV speckle-tracking strain, RV fraction area change (RVFAC), Tricuspid Annular Plane Systolic Excursion (TAPSE), pulmonary artery acceleration time (PAAT) and RV myocardial performance (Tei) index. Univariable and multivariable regression statistical analysis models were used. RESULTS: Out of 69 patients with acute PE, the median age was 55 and 48 % were female. The median body mass index (BMI) was 27 kg/m(2). Twenty-nine percent of the cohort had a history of cancer, with a significant increase in cancer prevalence in non-survivors (57 % vs 29 %, p = 0.02). Clinical parameters including heart rate, respiratory rate, troponin T level, active malignancy, hypertension and COPD were higher among non-survivors when compared to survivors (p ≤ 0.05). Using univariable analysis, NYHA class III symptoms, hypoxemia on presentation, tachycardia, tachypnea, elevation in Troponin T, absence of hypertension, active malignancy and chronic obstructive pulmonary disease (COPD) were increased in non-survivors compared to survivors (p ≤ 0.05). In multivariable models, RV Tei Index, global and free (lateral) wall RVLS were found to be negatively associated with survival probability after adjusting for age, gender and systolic blood pressure (p ≤ 0.05). CONCLUSION: The addition of echocardiographic assessment of RV function to clinical parameters improved the prediction of outcomes for patients with acute PE. Larger studies are needed to validate these findings.Item Open Access Commentary: Shunted single-ventricle neonatal ventricular-assist device support: Are we nearing a consensus strategy?(The Journal of thoracic and cardiovascular surgery, 2019-08) Andersen, Nicholas D; Kirmani, Sonya; Turek, Joseph WItem Open Access Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes.(Circ Res, 1999-01-08) Xiao, RP; Avdonin, P; Zhou, YY; Cheng, H; Akhter, SA; Eschenhagen, T; Lefkowitz, RJ; Koch, WJ; Lakatta, EG-Transgenic mouse models have been developed to manipulate beta-adrenergic receptor (betaAR) signal transduction. Although several of these models have altered betaAR subtypes, the specific functional sequelae of betaAR stimulation in murine heart, particularly those of beta2-adrenergic receptor (beta2AR) stimulation, have not been characterized. In the present study, we investigated effects of beta2AR stimulation on contraction, [Ca2+]i transient, and L-type Ca2+ currents (ICa) in single ventricular myocytes isolated from transgenic mice overexpressing human beta2AR (TG4 mice) and wild-type (WT) littermates. Baseline contractility of TG4 heart cells was increased by 3-fold relative to WT controls as a result of the presence of spontaneous beta2AR activation. In contrast, beta2AR stimulation by zinterol or isoproterenol plus a selective beta1-adrenergic receptor (beta1AR) antagonist CGP 20712A failed to enhance the contractility in TG4 myocytes, and more surprisingly, beta2AR stimulation was also ineffective in increasing contractility in WT myocytes. Pertussis toxin (PTX) treatment fully rescued the ICa, [Ca2+]i, and contractile responses to beta2AR agonists in both WT and TG4 cells. The PTX-rescued murine cardiac beta2AR response is mediated by cAMP-dependent mechanisms, because it was totally blocked by the inhibitory cAMP analog Rp-cAMPS. These results suggest that PTX-sensitive G proteins are responsible for the unresponsiveness of mouse heart to agonist-induced beta2AR stimulation. This was further corroborated by an increased incorporation of the photoreactive GTP analog [gamma-32P]GTP azidoanilide into alpha subunits of Gi2 and Gi3 after beta2AR stimulation by zinterol or isoproterenol plus the beta1AR blocker CGP 20712A. This effect to activate Gi proteins was abolished by a selective beta2AR blocker ICI 118,551 or by PTX treatment. Thus, we conclude that (1) beta2ARs in murine cardiac myocytes couple to concurrent Gs and Gi signaling, resulting in null inotropic response, unless the Gi signaling is inhibited; (2) as a special case, the lack of cardiac contractile response to beta2AR agonists in TG4 mice is not due to a saturation of cell contractility or of the cAMP signaling cascade but rather to an activation of beta2AR-coupled Gi proteins; and (3) spontaneous beta2AR activation may differ from agonist-stimulated beta2AR signaling.Item Open Access Home is Where the Heart Is: Interstage Home Monitoring in Infants With Single-Ventricle Heart Disease.(Journal of cardiothoracic and vascular anesthesia, 2021-10) Andrews, Jon S; Machovec, Kelly AItem Open Access In vivo ventricular gene delivery of a beta-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction.(Circulation, 2001-03-06) Shah, AS; White, DC; Emani, S; Kypson, AP; Lilly, RE; Wilson, K; Glower, DD; Lefkowitz, RJ; Koch, WJBACKGROUND: Genetic manipulation to reverse molecular abnormalities associated with dysfunctional myocardium may provide novel treatment. This study aimed to determine the feasibility and functional consequences of in vivo beta-adrenergic receptor kinase (betaARK1) inhibition in a model of chronic left ventricular (LV) dysfunction after myocardial infarction (MI). METHODS AND RESULTS: Rabbits underwent ligation of the left circumflex (LCx) marginal artery and implantation of sonomicrometric crystals. Baseline cardiac physiology was studied 3 weeks after MI; 5x10(11) viral particles of adenovirus was percutaneously delivered through the LCx. Animals received transgenes encoding a peptide inhibitor of betaARK1 (Adeno-betaARKct) or an empty virus (EV) as control. One week after gene delivery, global LV and regional systolic function were measured again to assess gene treatment. Adeno-betaARKct delivery to the failing heart through the LCx resulted in chamber-specific expression of the betaARKct. Baseline in vivo LV systolic performance was improved in Adeno-betaARKct-treated animals compared with their individual pre-gene delivery values and compared with EV-treated rabbits. Total beta-AR density and betaARK1 levels were unchanged between treatment groups; however, beta-AR-stimulated adenylyl cyclase activity in the LV was significantly higher in Adeno-betaARKct-treated rabbits compared with EV-treated animals. CONCLUSIONS: In vivo delivery of Adeno-betaARKct is feasible in the infarcted/failing heart by coronary catheterization; expression of betaARKct results in marked reversal of ventricular dysfunction. Thus, inhibition of betaARK1 provides a novel treatment strategy for improving the cardiac performance of the post-MI heart.Item Open Access Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart : prospects for molecular ventricular assistance.(Circulation, 2000-02-01) Glower, Donald D Jr; Hata, Jonathan Andrew; Koch, Walter J; Kypson, Alan P; Lefkowitz, Robert J; Lilly, R Eric; Pippen, Anne; Shah, AS; Silvestry, Scott Christopher; Tai, OliverBACKGROUND: Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human beta(2)AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. METHODS AND RESULTS: Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-betaGal) or the beta(2)AR (Adeno-beta(2)AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-beta(2)AR resulted in approximately 10-fold overexpression in a chamber-specific manner. Delivery of Adeno-betaGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of beta(2)ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. CONCLUSIONS: Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the beta(2)AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.Item Open Access It's not the heart: autonomic nervous system predisposition to lethal ventricular arrhythmias.(Heart rhythm, 2015-11) Landstrom, AP; Sun, JJ; Ray, RS; Wehrens, XHTItem Open Access Long Term Consequences of the Fontan Procedure and How to Manage Them.(Progress in cardiovascular diseases, 2018-09-17) Kay, W Aaron; Moe, Tabitha; Suter, Blair; Tennancour, Andrea; Chan, Alice; Krasuski, Richard A; Zaidi, Ali NIn 1971, Fontan and Baudet described a surgical technique for successful palliation of patients with tricuspid atresia. Subsequently, this technique has been applied to treat most forms of functional single ventricles and has become the current standard of care for long-term palliation of all patients with single ventricle congenital heart disease. Since 1971, the Fontan procedure has undergone several variations. These patients require lifelong management including a thorough knowledge of their anatomic substrate, hemodynamic status, management of rhythm and ventricular function along with multi organ evaluation. As these patients enter middle age, there is increasing awareness regarding the long-term complications and mortality. This review highlights the long-term outcomes of the Fontan procedure and management of late sequelae.Item Open Access LV Mass as a Predictor of CVD Events in Older Adults With and Without Metabolic Syndrome and Diabetes.(JACC. Cardiovascular imaging, 2015-09) Hoang, Khiet; Zhao, Yanglu; Gardin, Julius M; Carnethon, Mercedes; Mukamal, Ken; Yanez, David; Wong, Nathan DObjectives
The purpose of this study was to examine the prognostic significance of left ventricular (LV) mass for cardiovascular disease (CVD) events in older adults with and without metabolic syndrome (MetS) and diabetes mellitus (DM).Background
MetS and DM are associated with increased CVD risk, but it is unclear in these groups whether subclinical CVD as shown by increased LV mass improves risk prediction compared to standard risk factors in older individuals.Methods
We studied 3,724 adults (mean 72.4 ± 5.4 years of age, 61.0% female, 4.4% African-American) from the Cardiovascular Health Study who had MetS but not DM or had DM alone or had neither condition. Cox regression was used to examine the association of LV mass, (alone and indexed by height and body surface area [BSA]) as determined by echocardiography, with CVD events, including coronary heart disease (CHD), stroke, heart failure (HF), and CVD death, as well as total mortality. We also assessed the added prediction, discriminative value, and net reclassification improvement (NRI) for clinical utility of LV mass compared to standard risk factors.Results
Over a mean follow-up of 14.2 ± 6.3 years, 2,180 subjects experienced CVD events, including 986 CVD deaths. After adjustment for age, sex and standard risk factors, LV mass was positively associated with CVD events in those with MetS (hazard ratio [HR]: 1.4, p < 0.001) and without MetS (HR: 1.4, p < 0.001), but not DM (HR: 1.0, p = 0.62), with similar findings for LV mass indexed for height or BSA. Adding LV mass to standard risk factors moderately improved the prediction accuracy in the overall sample and MetS group from changes in C-statistics (p < 0.05). Categorical-free net reclassification improvement increased significantly by 17% to 19% in those with MetS. Findings were comparable for CHD, CVD mortality, and total mortality.Conclusions
LV mass is associated with increased CVD risk and provides modest added prediction and clinical utility compared to standard risk factors in older persons with and without MetS but not with DM.Item Open Access Modified INOvent for delivery of inhaled nitric oxide during cardiac MRI.(Magn Reson Imaging, 2011-10) Devendra, Ganesh P; Hart, Stephen A; Kim, Yuli Y; Setser, Randy M; Flamm, Scott D; Krasuski, Richard ABACKGROUND: The aim of this study was to assess the feasibility of delivering NO through a modified system to allow clearance of the magnetic field and thus compatibility with cardiac magnetic resonance (CMR). Nitric oxide (NO) is an inhalational, selective pulmonary vasodilator with a wide range of applications in a variety of disease states, including diseases that affect the right ventricle. Accurate assessment of dynamic changes in right ventricular function necessitates CMR; however, delivery of NO is only possible using equipment that is not magnetic resonance imaging (MRI) compatible (INOvent delivery system, Ohmeda, Inc., Madison, WI, USA). METHODS: The INOvent delivery system was modified by using 35 ft. of standard oxygen tubing to allow NO delivery through an electrical conduit and into the MRI suite. The concentrations of oxygen (O(2)), nitrogen dioxide (a harmful byproduct, NO(2)) and NO were measured in triplicate using the built-in electrochemical analyzer on the INOvent. After confirmation of safety, the system was used to administer drug to a patient x, and dynamic MRI measurements were performed. RESULTS: When the standard INOvent was set to administer 40 ppm of NO, the mean/standard deviation of gas delivered was as follows: NO: 42/0 ppm; NO(2): 0.3/0.1 ppm; and O(2): 93/0 ppm. In comparison, the gas delivery of the modified INOvent was follows: NO: 41/0 ppm; NO(2): 0.5/0 ppm; and O(2): 93.7/0.6 ppm. During administration to an index patient with severe pulmonic insufficiency (PI), a measurable reduction in PI was observed by CMR. CONCLUSIONS: Nitric oxide can be administered through 35 ft. of standard oxygen tubing without significantly affecting dose delivery. This technique has potential application in patients with right-sided structural heart disease for determination of dynamic physiological changes.Item Open Access Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases.(Proc Natl Acad Sci U S A, 1996-07-23) Oppermann, M; Diversé-Pierluissi, M; Drazner, MH; Dyer, SL; Freedman, NJ; Peppel, KC; Lefkowitz, RJGuanine nucleotide-binding regulatory protein (G protein)-coupled receptor kinases (GRKs) constitute a family of serine/threonine kinases that play a major role in the agonist-induced phosphorylation and desensitization of G-protein-coupled receptors. Herein we describe the generation of monoclonal antibodies (mAbs) that specifically react with GRK2 and GRK3 or with GRK4, GRK5, and GRK6. They are used in several different receptor systems to identify the kinases that are responsible for receptor phosphorylation and desensitization. The ability of these reagents to inhibit GRK- mediated receptor phosphorylation is demonstrated in permeabilized 293 cells that overexpress individual GRKs and the type 1A angiotensin II receptor. We also use this approach to identify the endogenous GRKs that are responsible for the agonist-induced phosphorylation of epitope-tagged beta2- adrenergic receptors (beta2ARs) overexpressed in rabbit ventricular myocytes that are infected with a recombinant adenovirus. In these myocytes, anti-GRK2/3 mAbs inhibit isoproterenol-induced receptor phosphorylation by 77%, while GRK4-6-specific mAbs have no effect. Consistent with the operation of a betaAR kinase-mediated mechanism, GRK2 is identified by immunoblot analysis as well as in a functional assay as the predominant GRK expressed in these cells. Microinjection of GRK2/3-specific mAbs into chicken sensory neurons, which have been shown to express a GRK3-like protein, abolishes desensitization of the alpha2AR-mediated calcium current inhibition. The intracellular inhibition of endogenous GRKs by mAbs represents a novel approach to the study of receptor specificities among GRKs that should be widely applicable to many G-protein-coupled receptors.Item Open Access Myocardial expression of a constitutively active alpha 1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy.(Proc Natl Acad Sci U S A, 1994-10-11) Milano, CA; Dolber, PC; Rockman, HA; Bond, RA; Venable, ME; Allen, LF; Lefkowitz, RJTransgenic mice were generated by using the alpha-myosin heavy chain promoter coupled to the coding sequence of a constitutively active mutant alpha 1B-adrenergic receptor (AR). These transgenic animals demonstrated cardiac-specific expression of this alpha 1-AR with resultant activation of phospholipase C as shown by increased myocardial diacylglycerol content. A phenotype consistent with cardiac hypertrophy developed in adult transgenic mice with increased heart/body weight ratios, myocyte cross-sectional areas, and ventricular atrial natriuretic factor mRNA levels relative to nontransgenic controls. These transgenic animals may provide insight into the biochemical triggers that induce hypertrophy in cardiac disease and serve as a convenient experimental model for studies of this condition.Item Open Access Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish.(Elife, 2015-04-01) Gemberling, Matthew; Karra, Ravi; Dickson, Amy L; Poss, Kenneth DHeart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program.Item Open Access Outcomes of Cardiac Resynchronization Therapy with Image-Guided Left Ventricular Lead Placement at the Site of Latest Mechanical Activation: A Systematic Review and Meta-Analysis.(Journal of interventional cardiology, 2022-01) Allen LaPointe, Nancy M; Ali-Ahmed, Fatima; Dalgaard, Frederik; Kosinski, Andrzej S; Schmidler, Gillian Sanders; Al-Khatib, Sana MAim
To assess evidence for an image-guided approach for cardiac resynchronization therapy (CRT) that targets left ventricular (LV) lead placement at the segment of latest mechanical activation.Methods
A systematic review of EMBASE and PubMed was performed for randomized controlled trials (RCTs) and prospective observational studies from October 2008 through October 2020 that compared an image-guided CRT approach with a non-image-guided approach for LV lead placement. Meta-analyses were performed to assess the association between the image-guided approach and NYHA class improvement or changes in end-systolic volume (LVESV), end-diastolic volume (LVEDV), and ejection fraction (LVEF).Results
From 5897 citations, 5 RCTs including 818 patients (426 image-guided and 392 non-image-guided) were identified. The mean age ranged from 66 to 71 years, 76% were male, and 53% had ischemic cardiomyopathy. Speckle tracking echocardiography was the primary image-guided method in all studies. LV lead placement within the segment of the latest mechanical activation (concordant) was achieved in the image-guided arm in 45% of the evaluable patients. There was a statistically significant improvement in the NYHA class at 6 months (odds ratio 1.66; 95% confidence interval (CI) [1.02, 2.69]) with the image-guided approach, but no statistically significant change in LVESV (MD -7.1%; 95% CI [-16.0, 1.8]), LVEDV (MD -5.2%; 95% CI [-15.8, 5.4]), or LVEF (MD 0.68; 95% CI [-4.36, 5.73]) versus the non-image-guided approach.Conclusion
The image-guided CRT approach was associated with improvement in the NYHA class but not echocardiographic measures, possibly due to the small sample size and a low rate of concordant LV lead placement despite using the image-guided approach. Therefore, our meta-analysis was not able to identify consistent improvement in CRT outcomes with an image-guided approach.Item Open Access Phosphoproteomic profiling of human myocardial tissues distinguishes ischemic from non-ischemic end stage heart failure.(PLoS One, 2014) Schechter, Matthew A; Hsieh, Michael KH; Njoroge, Linda W; Thompson, J Will; Soderblom, Erik J; Feger, Bryan J; Troupes, Constantine D; Hershberger, Kathleen A; Ilkayeva, Olga R; Nagel, Whitney L; Landinez, Gina P; Shah, Kishan M; Burns, Virginia A; Santacruz, Lucia; Hirschey, Matthew D; Foster, Matthew W; Milano, Carmelo A; Moseley, M Arthur; Piacentino, Valentino; Bowles, Dawn EThe molecular differences between ischemic (IF) and non-ischemic (NIF) heart failure are poorly defined. A better understanding of the molecular differences between these two heart failure etiologies may lead to the development of more effective heart failure therapeutics. In this study extensive proteomic and phosphoproteomic profiles of myocardial tissue from patients diagnosed with IF or NIF were assembled and compared. Proteins extracted from left ventricular sections were proteolyzed and phosphopeptides were enriched using titanium dioxide resin. Gel- and label-free nanoscale capillary liquid chromatography coupled to high resolution accuracy mass tandem mass spectrometry allowed for the quantification of 4,436 peptides (corresponding to 450 proteins) and 823 phosphopeptides (corresponding to 400 proteins) from the unenriched and phospho-enriched fractions, respectively. Protein abundance did not distinguish NIF from IF. In contrast, 37 peptides (corresponding to 26 proteins) exhibited a ≥ 2-fold alteration in phosphorylation state (p<0.05) when comparing IF and NIF. The degree of protein phosphorylation at these 37 sites was specifically dependent upon the heart failure etiology examined. Proteins exhibiting phosphorylation alterations were grouped into functional categories: transcriptional activation/RNA processing; cytoskeleton structure/function; molecular chaperones; cell adhesion/signaling; apoptosis; and energetic/metabolism. Phosphoproteomic analysis demonstrated profound post-translational differences in proteins that are involved in multiple cellular processes between different heart failure phenotypes. Understanding the roles these phosphorylation alterations play in the development of NIF and IF has the potential to generate etiology-specific heart failure therapeutics, which could be more effective than current therapeutics in addressing the growing concern of heart failure.