Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue.

Abstract:

BACKGROUND:Modeling of human arrhythmias with induced pluripotent stem cell-derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported. METHODS:Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell-derived cardiomyocyte-based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing. RESULTS:In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca2+ levels and increased temporal and spatial dispersion of Ca2+ wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor-serine 2814 phosphorylation by Ca2+/calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues. CONCLUSIONS:Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II-dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.

journal_name

Circulation

journal_title

Circulation

authors

Park SJ,Zhang D,Qi Y,Li Y,Lee KY,Bezzerides VJ,Yang P,Xia S,Kim SL,Liu X,Lu F,Pasqualini FS,Campbell PH,Geva J,Roberts AE,Kleber AG,Abrams DJ,Pu WT,Parker KK

doi

10.1161/CIRCULATIONAHA.119.039711

subject

Has Abstract

pub_date

2019-07-30 00:00:00

pages

390-404

issue

5

eissn

0009-7322

issn

1524-4539

journal_volume

140

pub_type

杂志文章
  • Postoperative investigation of left ventricular aneurysm resection.

    abstract::We reviewed 35 patients undergoing resection of a chronic postinfarction left ventricular aneurysm. There was 5.7% operative mortality. Of the long-term survivors, 80% are functional class I or II. Ten patients had postoperative left ventriculograms studied by means of a computerized analysis of endocardial motion usi...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:

    authors: Shaw RC,Connors JP,Hieb BR,Ludbrook PA,Krone R,Kleiger RE,Ferguson TB,Weldon CS

    更新日期:1977-09-01 00:00:00

  • Coronary vasomotor effects of serotonin in patients with angina. Relation to coronary stenosis morphology.

    abstract:BACKGROUND:Previous experimental studies have shown that the effect of serotonin on a coronary stenosis depends on whether that stenosis is compliant or fixed. However, the relation between coronary stenosis morphology and the response to serotonin in patients with angina is not known. METHODS AND RESULTS:Using comput...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.88.4.1518

    authors: Tousoulis D,Davies G,McFadden E,Clarke J,Kaski JC,Maseri A

    更新日期:1993-10-01 00:00:00

  • In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation: a clue to the understanding of the mechanisms of thrombotic plaque erosion.

    abstract:BACKGROUND:The mechanisms of thrombosis on plaque erosion are poorly understood. We examined the potential role of endothelial apoptosis in endothelial erosion and vessel thrombosis. METHODS AND RESULTS:Segments of New Zealand White rabbit femoral arteries were temporarily isolated in vivo. One artery was incubated wi...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.CIR.0000130172.62481.90

    authors: Durand E,Scoazec A,Lafont A,Boddaert J,Al Hajzen A,Addad F,Mirshahi M,Desnos M,Tedgui A,Mallat Z

    更新日期:2004-06-01 00:00:00

  • Analysis of ventricular activation using surface electrocardiography to predict left ventricular reverse volumetric remodeling during cardiac resynchronization therapy.

    abstract:BACKGROUND:Cardiac resynchronization therapy for heart failure with left bundle branch block reduces left ventricular (LV) conduction delay, contraction asynchrony, and LV end-systolic volume ("reverse remodeling"). Up to one third of patients do not improve, and the electric requirements for reverse remodeling are unc...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/CIRCULATIONAHA.109.894774

    authors: Sweeney MO,van Bommel RJ,Schalij MJ,Borleffs CJ,Hellkamp AS,Bax JJ

    更新日期:2010-02-09 00:00:00

  • Estrogen receptors alpha and beta mediate contribution of bone marrow-derived endothelial progenitor cells to functional recovery after myocardial infarction.

    abstract:BACKGROUND:Estradiol (E2) modulates the kinetics of circulating endothelial progenitor cells (EPCs) and favorably affects neovascularization after ischemic injury. However, the roles of estrogen receptors alpha (ER alpha) and beta (ER beta) in EPC biology are largely unknown. METHODS AND RESULTS:In response to E2, mig...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/CIRCULATIONAHA.106.631465

    authors: Hamada H,Kim MK,Iwakura A,Ii M,Thorne T,Qin G,Asai J,Tsutsumi Y,Sekiguchi H,Silver M,Wecker A,Bord E,Zhu Y,Kishore R,Losordo DW

    更新日期:2006-11-21 00:00:00

  • First postpacing interval variability during right ventricular stimulation: a single algorithm for the differential diagnosis of regular tachycardias.

    abstract:BACKGROUND:Failure to differentiate supraventricular from ventricular arrhythmias is the most frequent cause of inappropriate implantable cardioverter-defibrillator therapies. Although a sudden-onset criterion is available to differentiate sustained monomorphic ventricular tachycardias (SMVTs) and sinus tachycardias (S...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.98.7.671

    authors: Arenal A,Almendral J,Villacastin J,Morris R,Castellanos E,Delcan JL

    更新日期:1998-08-18 00:00:00

  • Comparative effects of nicardipine, a new calcium antagonist, on size of myocardial infarction after coronary artery occlusion in dogs.

    abstract::To examine whether nicardipine, a dihydropyridine derivative, limits size of myocardial infarction, and to compare the protective effects of nicardipine administered before and early and late after coronary artery occlusion, 99mTc-labeled albumin microspheres were injected into the left atrium during 5 min temporary c...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.74.2.420

    authors: Endo T,Nejima J,Fujita S,Kiuchi K,Iida N,Kikuchi K,Hayakawa H,Okumura H

    更新日期:1986-08-01 00:00:00

  • Prognosis of retrograde dissection from the descending to the ascending aorta.

    abstract:BACKGROUND:Natural history of aortic dissection (AD) with intimal tear in the descending or abdominal aorta and retrograde extension into the ascending aorta (retrograde AD) remains unknown. The purpose of this study was to elucidate medium-term prognosis of patients with retrograde AD. METHODS AND RESULTS:Study popul...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.0000087424.32901.98

    authors: Kaji S,Akasaka T,Katayama M,Yamamuro A,Yamabe K,Tamita K,Akiyama M,Watanabe N,Tanemoto K,Morioka S,Yoshida K

    更新日期:2003-09-09 00:00:00

  • Myocardial infarction size from serial CPK: variability of CPK serum entry ratio with size and model of infarction.

    abstract::To study the variability of the fraction of CPK released from the infarcted heart which enters the serum (serum entry ratio, or SER) with size and model of infarction, nine dogs underwent homogeneous infarctions (LAD ligation) of varying sizes, and 10 dogs underwent scattered infarctions (left coronary embolization). ...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.58.6.1143

    authors: Cairns JA,Missirlis E,Fallen EL

    更新日期:1978-12-01 00:00:00

  • Should a fixed external reference system be used to analyze left ventricular wall motion?

    abstract::To investigate whether a fixed external reference system should be used to most accurately describe regional left ventricular wall motion, we used vectors to analyze a simple model of ventricular contraction. If measured in a fixed external reference system, motion of implanted radiopaque midwall markers may contain t...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.65.7.1518

    authors: Clayton PD,Jeppson GM,Klausner SC

    更新日期:1982-06-01 00:00:00

  • Bypass surgery with the internal mammary artery graft: 15 year follow-up.

    abstract::We performed a 15 year follow-up of 748 patients undergoing bypass surgery, comparing 532 patients with one or two internal mammary artery grafts with or without additional saphenous vein grafts to 216 patients with saphenous vein grafts alone. During the 15 years of follow-up the 532 patients with at least one intern...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:

    authors: Cameron A,Kemp HG Jr,Green GE

    更新日期:1986-11-01 00:00:00

  • Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial.

    abstract:BACKGROUND:Many patients with implanted cardioverter defibrillators (ICDs) receive adjunctive antiarrhythmic drug therapy, most commonly amiodarone or sotalol. The effects of these drugs on defibrillation energy requirements have not been previously assessed in a randomized controlled trial. METHODS AND RESULTS:The Op...

    journal_title:Circulation

    pub_type: 杂志文章,随机对照试验

    doi:10.1161/CIRCULATIONAHA.106.618421

    authors: Hohnloser SH,Dorian P,Roberts R,Gent M,Israel CW,Fain E,Champagne J,Connolly SJ

    更新日期:2006-07-11 00:00:00

  • Public policy on smoking and health: toward a smoke-free generation by the year 2000. A statement of a working group to the Subcommittee on Smoking of the American Heart Association.

    abstract::On May 20, 1984, the Surgeon General challenged the health community to work toward attainment of a smoke-free society by the year 2000. The leadership of the nation's three major voluntary organizations joined numerous associations of health professionals in accepting the challenge. The Subcommittee on Smoking of the...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:

    authors: Warner KE,Ernster VL,Holbrook JH,Lewit EM,Pertschuk M,Steinfeld JL,Whelan EM

    更新日期:1986-02-01 00:00:00

  • Peroxisome proliferator-activated receptor gamma plays a critical role in inhibition of cardiac hypertrophy in vitro and in vivo.

    abstract:BACKGROUND:Peroxisome proliferator-activated receptors (PPARs) are transcription factors of the nuclear receptor superfamily. It has been reported that the thiazolidinediones, which are antidiabetic agents and high-affinity ligands for PPARgamma, regulate growth of vascular cells. In the present study, we examined the ...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/hc1002.105225

    authors: Asakawa M,Takano H,Nagai T,Uozumi H,Hasegawa H,Kubota N,Saito T,Masuda Y,Kadowaki T,Komuro I

    更新日期:2002-03-12 00:00:00

  • Contributory mechanisms for the beneficial effects of myocyte preconditioning during cardioplegic arrest.

    abstract:BACKGROUND:Preconditioning protects the myocardium from ischemia and may be a potent means of endogenous cardioprotection during cardioplegic arrest and rewarming. However, fundamental mechanisms that potentially contribute to the beneficial effects of preconditioning during cardioplegic arrest and rewarming remain unc...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:

    authors: O SJ,Zellner JL,Cox MH,Hebbar L,Brothers TE,Mukherjee R,Tempel GE,Dorman BH,Crawford FA Jr,Spinale FG

    更新日期:1996-11-01 00:00:00

  • Neuropsychological outcome after percutaneous coronary intervention or coronary artery bypass grafting: results from the Stent or Surgery (SoS) Trial.

    abstract:BACKGROUND:Coronary artery bypass surgery (CABG) has been associated with a range of neurological and neuropsychological complications from stroke to cognitive problems such as memory and problem solving disturbance. However, little is known about the impact of percutaneous coronary intervention (PCI) on neuropsycholog...

    journal_title:Circulation

    pub_type: 临床试验,杂志文章,多中心研究,随机对照试验

    doi:10.1161/01.CIR.0000148366.80443.2B

    authors: Währborg P,Booth JE,Clayton T,Nugara F,Pepper J,Weintraub WS,Sigwart U,Stables RH,SoS Neuropsychology Substudy Investigators.

    更新日期:2004-11-30 00:00:00

  • Long-term benefit of postconditioning.

    abstract:BACKGROUND:We previously demonstrated that ischemic postconditioning decreases creatine kinase release, a surrogate marker for infarct size, in patients with acute myocardial infarction. Our objective was to determine whether ischemic postconditioning could afford (1) a persistent infarct size limitation and (2) an imp...

    journal_title:Circulation

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1161/CIRCULATIONAHA.107.729780

    authors: Thibault H,Piot C,Staat P,Bontemps L,Sportouch C,Rioufol G,Cung TT,Bonnefoy E,Angoulvant D,Aupetit JF,Finet G,André-Fouët X,Macia JC,Raczka F,Rossi R,Itti R,Kirkorian G,Derumeaux G,Ovize M

    更新日期:2008-02-26 00:00:00

  • Ventricular expression of brain natriuretic peptide in hypertrophic cardiomyopathy.

    abstract:BACKGROUND:Brain natriuretic peptide (BNP), as a cardiac hormone, is expressed together with atrial natriuretic peptide (ANP) in the ventricles in congestive heart failure. However, the ventricular expression of BNP in hypertrophic cardiomyopathy (HCM) with normal systolic function is still unclear. METHODS AND RESULT...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.88.2.372

    authors: Hasegawa K,Fujiwara H,Doyama K,Miyamae M,Fujiwara T,Suga S,Mukoyama M,Nakao K,Imura H,Sasayama S

    更新日期:1993-08-01 00:00:00

  • Spontaneous occurrence of symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia in untreated patients.

    abstract:BACKGROUND:Ambulatory outpatients (n = 150) with a history of paroxysmal supraventricular arrhythmia were studied to establish the characteristics of the first recurrence of symptomatic tachycardia (time to first recurrence, heart rate during tachycardia, and observed rhythm that was regular versus irregular) when no a...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.87.4.1114

    authors: Clair WK,Wilkinson WE,McCarthy EA,Page RL,Pritchett EL

    更新日期:1993-04-01 00:00:00

  • Early atrial fibrillation during evolving myocardial infarction: a consequence of impaired left atrial perfusion.

    abstract::Seven of 214 patients (3%) with acute myocardial infarction (120 inferior and 94 anterior) developed atrial fibrillation within 3 hr of the onset of chest pain. All seven patients had an inferior infarction and in all seven the left circumflex artery was occluded proximal to the origin of its left atrial circumflex br...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.75.1.146

    authors: Hod H,Lew AS,Keltai M,Cercek B,Geft IL,Shah PK,Ganz W

    更新日期:1987-01-01 00:00:00

  • Attenuation of exercise-induced myocardial ischemia in dogs with recruitment of coronary vasodilator reserve by nifedipine.

    abstract::There is now evidence that under resting conditions coronary vasodilator reserve exists even in the presence of myocardial ischemia. Therefore, we tested the hypothesis that a vasodilator reserve may exist during exercise so that during exercise-induced ischemia a reduction in coronary constrictor tone can be produced...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.75.2.482

    authors: Heusch G,Guth BD,Seitelberger R,Ross J Jr

    更新日期:1987-02-01 00:00:00

  • Pharmacoangiographic manipulation of renal collateral blood flow.

    abstract::Vasodilatory or vasoconstrictive renal pharmacoangiography was applied in investigating the significance of 50 renal artery stenoses. The technique involves comparison of selective magnification renal arteriograms before and after intra-arterial injection of epinephrine or acetylcholine, seeking changes in direction o...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.54.2.328

    authors: Bookstein JJ,Walter JF,Stanley JC,Fry WJ

    更新日期:1976-08-01 00:00:00

  • Circulating transforming growth factor-beta in Marfan syndrome.

    abstract:BACKGROUND:Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-beta (TGF-beta). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-beta activation, may be an effective treatment for MFS. We hypothesized that dysregula...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/CIRCULATIONAHA.108.841981

    authors: Matt P,Schoenhoff F,Habashi J,Holm T,Van Erp C,Loch D,Carlson OD,Griswold BF,Fu Q,De Backer J,Loeys B,Huso DL,McDonnell NB,Van Eyk JE,Dietz HC,GenTAC Consortium.

    更新日期:2009-08-11 00:00:00

  • Electrocardiographic and hemodynamic changes in experimental right ventricular infarction.

    abstract::To investigate the electrocardiographic and hemodynamic changes in isolated right ventricular infarction, 0.25 ml or 0.5 ml of metallic mercury was injected into the right coronary artery of 14 closed-chest dogs. At autopsy, at least 60% of the right ventricle was necrotic in every dog. Hemodynamic observations were m...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.67.6.1258

    authors: Chou TC,Fowler NO,Gabel M,van der Bel-Kahn J,Feltner EJ

    更新日期:1983-06-01 00:00:00

  • A prospective study of nutritional factors and hypertension among US men.

    abstract:BACKGROUND:An effect of diet in determining blood pressure is suggested by epidemiological studies, but the role of specific nutrients is still unsettled. METHODS AND RESULTS:The relation of various nutritional factors with hypertension was examined prospectively among 30,681 predominantly white US male health profess...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.86.5.1475

    authors: Ascherio A,Rimm EB,Giovannucci EL,Colditz GA,Rosner B,Willett WC,Sacks F,Stampfer MJ

    更新日期:1992-11-01 00:00:00

  • Hemodynamic effects of labetalol, an alpha and beta adrenergic blocking agent, in hypertensive subjects.

    abstract::Labetalol was administered to six hypertensive subjects in increasing doses for seven days. A decrease in both supine and standing arterial pressure and heart rate was observed with no change in cardiac output and few side effects. Exercise tolerance was unaltered by the drug, but the heart rate and arterial pressure ...

    journal_title:Circulation

    pub_type: 临床试验,杂志文章

    doi:10.1161/01.cir.55.2.370

    authors: Mehta J,Cohn JN

    更新日期:1977-02-01 00:00:00

  • Long-term mitral valve replacement in young children. Influence of somatic growth on prosthetic valve adequacy.

    abstract::Long-term clinical and laboratory findings in three children who required mitral valve replacement below age four years are reported. In each instance a second valve replacement was necessary approximately 8 1/2 years after the initial one, following a two and one-half fold increase in body weight. Inadequate mitral v...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.57.5.981

    authors: Friedman S,Edmunds LH Jr,Cuaso CC

    更新日期:1978-05-01 00:00:00

  • Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis.

    abstract:BACKGROUND:A positive association was previously reported between angiotensin-converting enzyme (ACE) gene polymorphism and several cardiovascular diseases, such as myocardial infarction, left ventricular hypertrophy, and restenosis after percutaneous transluminal coronary angioplasty. Plasma ACE activity and carotid-w...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/01.cir.91.4.951

    authors: Ishigami T,Umemura S,Iwamoto T,Tamura K,Hibi K,Yamaguchi S,Nyuui N,Kimura K,Miyazaki N,Ishii M

    更新日期:1995-02-15 00:00:00

  • Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population.

    abstract:BACKGROUND:Oxidized LDL (oxLDL) is thought to play a key role in the inflammatory response in the arterial vessel wall. METHODS AND RESULTS:In a prospective, nested, case-control study, the association between plasma oxLDL and risk of an acute coronary heart disease (CHD) event was investigated in men without prevalen...

    journal_title:Circulation

    pub_type: 杂志文章

    doi:10.1161/CIRCULATIONAHA.104.529297

    authors: Meisinger C,Baumert J,Khuseyinova N,Loewel H,Koenig W

    更新日期:2005-08-02 00:00:00

  • Exercise-induced myocardial ischemia in a cold environment. Effect of antianginal medications.

    abstract::The influence of cold on the threshold for myocardial ischemia and the efficacy of antianginal drugs in a cold environment were assessed in 24 patients with stable angina and exercise-induced ST depression. Treadmill exercise tests were done according to a randomized double-blind protocol 90 minutes after administrati...

    journal_title:Circulation

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1161/01.cir.79.5.1015

    authors: Juneau M,Johnstone M,Dempsey E,Waters DD

    更新日期:1989-05-01 00:00:00