Muscle-derived stem cell sheets support pump function and prevent cardiac arrhythmias in a model of chronic myocardial infarction.
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ABSTRACT:
SUBMITTER: Sekiya N
PROVIDER: S-EPMC3589171 | biostudies-other | 2013 Mar
REPOSITORIES: biostudies-other
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Project description:Arrhythmias are a hallmark of myocardial infarction (MI) and increase patient mortality. The cardiac conduction system is implicated in arrhythmias, but how it is altered following MI is poorly understood. We demonstrate complete conduction system restoration during neonatal mouse heart regeneration, versus pathological remodelling at non-regenerative stages. Tissue-cleared whole-organ imaging identified disorganised bundling of conduction fibres after MI, global His/Purkinje disruption and regional loss of connexin-40. Single-cell RNA-sequencing revealed that Purkinje cells undergo specific molecular changes to regenerate the network, versus sustained aberrant electrical alterations during fibrotic repair. This manifested functionally as transition from normal rhythm to pathological conduction delay beyond the regenerative window. Modelling the non-regenerative phenotype in the infarcted human heart implicated these changes as causative for bundle branch block and ventricular dyssynchrony, as observed in patients. These findings elucidate the mechanisms underpinning conduction system regeneration versus repair and reveal the consequences of MI-induced damage for clinical arrhythmogenesis.
2024-10-31 | GSE245872 | GEO
Project description:Aims: To evaluate whether low level left vagus nerve stimulation (LLVNS) in early stage of myocardial infarction (MI) could effectively prevent ventricular arrhythmias (VAs) and protect cardiac function, and explore the underlying mechanisms. Methods and Results: After undergoing implantable cardioverter defibrillators (ICD) and left cervical vagal stimulators implantation and MI creation, 16 dogs were randomly divided into three groups: the MI (n = 6), MI+LLVNS (n = 5), and sham operation (n = 5) groups. LLVNS was performed for 3 weeks. VAs, the left ventricular function, the density of the nerve fibers in the infarction area and gene expression profiles were analyzed. Compared with the MI group, dogs in the MI+LLVNS group had a lower VAs incidence (p < 0.05) and better left ventricular function. LLVNS significantly inhibited excessive sympathetic nerve sprouting with the evidences of decreased density of TH, GAP43 and NF positive nerves (p < 0.05). The gene expression profiling found a total of 206 genes differentially expressed between MI+LLVNS and MI dogs, mainly involved in cardiac tissue remodeling, cardiac neural remodeling, immune response and apoptosis. These genes, including 55 up-regulated genes and 151 down-regulated genes, showed more protective expressions under LLVNS. Conclusions: This study suggests that LLVNS was delivered without altering heart rate, contributing to reduced incidences of VAs and improved left ventricular function. The potential mechanisms included suppressing cardiac neuronal sprouting, inhibiting excessive sympathetic nerve sprouting and subduing pro-inflammatory responses by regulating gene expressions from a canine experimental study.
| S-EPMC8107219 | biostudies-literature
Project description:RATIONALE:Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined and are the focus of this study. OBJECTIVES:We developed a mouse model in which we could prevent depressed myocyte contractility after MI and used it to test the idea that preventing depression of myocyte Ca(2+)-handling defects could avert post-MI cardiac pump dysfunction. METHODS AND RESULTS:MI was produced in mice with inducible, cardiac-specific expression of the ?2a subunit of the L-type Ca(2+) channel. Myocyte and cardiac function were compared in control and ?2a animals before and after MI. ?2a myocytes had increased Ca(2+) current; sarcoplasmic reticulum Ca(2+) load, contraction and Ca(2+) transients (versus controls), and ?2a hearts had increased performance before MI. After MI, cardiac function decreased. However, ventricular dilation, myocyte hypertrophy and death, and depressed cardiac pump function were greater in ?2a versus control hearts after MI. ?2a animals also had poorer survival after MI. Myocytes isolated from ?2a hearts after MI did not develop depressed Ca(2+) handling, and Ca(2+) current, contractions, and Ca(2+) transients were still above control levels (before MI). CONCLUSIONS:Maintaining myocyte contractility after MI, by increasing Ca(2+) influx, depresses rather than improves cardiac pump function after MI by reducing myocyte number.
| S-EPMC3021375 | biostudies-literature
Project description:Elucidation of the physiologically distinct subunits of troponin in 1973 greatly facilitated our understanding of cardiac contraction. Although troponins are expressed in both skeletal and cardiac muscle, there are isoforms of troponin I/T expressed selectively in the heart. By exploiting cardiac-restricted epitopes within these proteins, one of the most successful diagnostic tests to date has been developed: cardiac troponin (cTn) assays. For the past decade, cTn has been regarded as the gold-standard marker for acute myocardial necrosis: the pathological hallmark of acute myocardial infarction (AMI). Whilst cTn is the cornerstone for ruling-out AMI in patients presenting with a suspected acute coronary syndrome (ACS), elevated cTn is frequently observed in those without clinical signs indicative of AMI, often reflecting myocardial injury of 'unknown origin'. cTn is commonly elevated in acute non-ACS conditions, as well as in chronic diseases. It is unclear why these elevations occur; yet they cannot be ignored as cTn levels in chronically unwell patients are directly correlated to prognosis. Paradoxically, improvements in assay sensitivity have meant more differential diagnoses have to be considered due to decreased specificity, since cTn is now more easily detected in these non-ACS conditions. It is important to be aware cTn is highly specific for myocardial injury, which could be attributable to a myriad of underlying causes, emphasizing the notion that cTn is an organ-specific, not disease-specific biomarker. Furthermore, the ability to detect increased cTn using high-sensitivity assays following extreme exercise is disconcerting. It has been suggested troponin release can occur without cardiomyocyte necrosis, contradicting conventional dogma, emphasizing a need to understand the mechanisms of such release. This review discusses basic troponin biology, the physiology behind its detection in serum, its use in the diagnosis of AMI, and some key concepts and experimental evidence as to why cTn can be elevated in chronic diseases.
| S-EPMC5852618 | biostudies-literature
Project description:Electrospun nanofibrous sheets get increasing attention in myocardial infarction (MI) treatment due to their good cytocompatibility to deliver transplanted stem cells to infarcted areas and due to mechanical characteristics to support damaged tissue. Cardiac extracellular matrix is essential for implanted cells since it provides the cardiac microenvironment. In this study, we hypothesized high concentrations of cardiac nature protein (NP), namely elastin and collagen, in hybrid polycaprolactone (PCL) electrospun nanofibrous sheets could be effective as cardiac-mimicking patch. Optimal ratio of elastin and collagen with PCL in electrospun sheets (80% NP/PCL) was selected based on cytocompatibility and mechanical characteristics. Bone-marrow (BM) c-kit(+) cells anchoring onto NP/PCL sheets exhibited increased proliferative capacity compared with those seeded on PCL in vitro. Moreover, we examined the improvement of cardiac function in MI mice by cell-seeded cardiac patch. Green Fluorescent Protein (GFP)-labeled BM c-kit(+) cells were loaded on 80% NP/PCL sheets which was transplanted into MI mice. Both 80% NP/PCL and c-kit(+)-seeded 80% NP/PCL effectively improved cardiac function after 4 weeks of transplantation, with reduced infarction area and restricted LV remodeling. C-kit(+)-seeded 80% NP/PCL was even superior to the 80% NP/PCL alone and both superior to PCL. GFP(+) cells were identified both in the sheets and local infarcted area where transplanted cells underwent cardiac differentiation after 4 weeks. To the best of our knowledge, this is the first report that sheets with high concentrations of nature proteins loaded with BM c-kit(+) cells might be a novel promising candidate for tissue-engineered cardiac patch to improve cardiac repair after MI.
| S-EPMC4859897 | biostudies-other
Project description:Heart repair by stem cell treatment may involve life-threatening arrhythmias. Cardiac progenitor cells (CPCs) appear best suited for reconstituting lost myocardium without posing arrhythmic risks, being commissioned towards cardiac phenotype. In this study we tested the hypothesis that mobilization of CPCs through locally delivered Hepatocyte Growth Factor and Insulin-Like Growth Factor-1 to heal chronic myocardial infarction (MI), lowers the proneness to arrhythmias. We used 133 adult male Wistar rats either with one-month old MI and treated with growth factors (GFs, n?=?60) or vehicle (V, n?=?55), or sham operated (n?=?18). In selected groups of animals, prior to and two weeks after GF/V delivery, we evaluated stress-induced ventricular arrhythmias by telemetry-ECG, cardiac mechanics by echocardiography, and ventricular excitability, conduction velocity and refractoriness by epicardial multiple-lead recording. Invasive hemodynamic measurements were performed before sacrifice and eventually the hearts were subjected to anatomical, morphometric, immunohistochemical, and molecular biology analyses. When compared with untreated MI, GFs decreased stress-induced arrhythmias and concurrently prolonged the effective refractory period (ERP) without affecting neither the duration of ventricular repolarization, as suggested by measurements of QTc interval and mRNA levels for K-channel ?-subunits Kv4.2 and Kv4.3, nor the dispersion of refractoriness. Further, markers of cardiomyocyte reactive hypertrophy, including mRNA levels for K-channel ?-subunit Kv1.4 and ?-subunit KChIP2, interstitial fibrosis and negative structural remodeling were significantly reduced in peri-infarcted/remote ventricular myocardium. Finally, analyses of BrdU incorporation and distribution of connexin43 and N-cadherin indicated that cytokines generated new vessels and electromechanically-connected myocytes and abolished the correlation of infarct size with deterioration of mechanical function. In conclusion, local injection of GFs ameliorates electromechanical competence in chronic MI. Reduced arrhythmogenesis is attributable to prolongation of ERP resulting from improved intercellular coupling via increased expression of connexin43, and attenuation of unfavorable remodeling.
| S-EPMC3060871 | biostudies-literature
Project description:Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias.
| S-EPMC4315356 | biostudies-literature
Project description:We investigated the effects of intermittent hypoxia (IH), such as that encountered in severe obstructive sleep apnea (OSA) patients, on the development and severity of myocardial ischemia-related ventricular arrhythmias. Rats were exposed to 14 days of IH (30?s at 5%O2 and 30?s at 21%O2, 8?h·day-1) or normoxia (N, similar air-air cycles) and submitted to a 30-min coronary ligature. Arterial blood pressure (BP) and ECG were recorded for power spectral analysis, ECG interval measurement and arrhythmia quantification. Left ventricular monophasic action potential duration (APD) and expression of L-type calcium (LTCC) and transient receptor potential (TRPC) channels were assessed in adjacent epicardial and endocardial sites. Chronic IH enhanced the incidence of ischemic arrhythmias, in particular ventricular fibrillation (66.7% vs. 33.3% in N rats, p?<?0.05). IH also increased BP and plasma norepinephine levels along with increased low-frequency (LF), decreased high-frequency (HF) and increased LF/HF ratio of heart rate and BP variability. IH prolonged QTc and Tpeak-to-Tend intervals, increased the ventricular APD gradient and upregulated endocardial but not epicardial LTCC, TRPC1 and TRPC6 (p?<?0.05). Chronic IH, is a major risk factor for sudden cardiac death upon myocardial ischemia through sympathoactivation and alterations in ventricular repolarization, transmural APD gradient and endocardial calcium channel expression.
| S-EPMC5813022 | biostudies-literature
Project description:AimOveractivation of the sympathetic nerve may lead to severe ventricular arrhythmias (VAs) after myocardial infarction (MI). Thus, targeting sympathetic nerve activity is an effective strategy to prevent VAs clinically. The superior cervical ganglion (SCG), the extracardiac sympathetic ganglion innervating cardiac muscles, has been found to have a GABAergic signalling system, the physiological significance of which is obscure. We aimed to explore the functional significance of SCG post MI and whether the GABAergic signal system is involved in the process.MethodsAdult male Sprague-Dawley rats were divided into seven different groups. Rats in the MI groups underwent ligation of the left anterior descending coronary artery. All animals were used for electrophysiological testing, renal sympathetic nerve activity (RSNA) testing, and ELISA. Primary SCG sympathetic neurons were used for the in vitro study.ResultsThe GABAA receptor agonist muscimol significantly decreased the ATP-induced increase in intracellular Ca2+ (P < 0.05). GABA treatment in MI rats significantly attenuated the level of serum and cardiac norepinephrine (NE; P < 0.05). Sympathetic activity and inducible VAs were also lower in MI + GABA rats than in MI rats (P < 0.05). Knockdown of the GABAA Rs β2 subunit (GABAA Rβ2 ) in the SCG of MI rats increased the NE levels in serum and cardiac tissue, RSNA and inducible VAs compared with vehicle shRNA (P < 0.05).ConclusionThe GABAergic signalling system is functionally expressed in SCG sympathetic neurons, and activation of this system suppresses sympathetic activity, thereby facilitating cardiac protection and making it a potential target to alleviate VAs.
| S-EPMC6813916 | biostudies-literature
Project description:IntroductionMyocardial infarction (MI) is associated with an increase in subsequent heart failure (HF), recurrent ischemic events, sudden cardiac arrest, and ventricular arrhythmias (SCA-VA). The primary objective of the study to determine the role of intercurrent HF and ischemic events on the development of SCA-VA following first type I MI.Methods and resultsA retrospective cohort study of patients experiencing first type 1 MI in Olmsted County, Minnesota (2002-2012) was conducted by identifying patients using the medical records linkage system (Rochester epidemiology project). Patients aged ≥18 years were followed from the time of MI till death or 31 July, 2017. Intercurrent HF and ischemic events were the primary exposures following MI and their association with outcome SCA-VA was assessed. Eight hundred and sixty-seven patients (mean age was 63 ± 14.5 years; 69% male; 49.8% ST-elevation myocardial infarction) who had their first type I MI during the study period were included. Majority of acute MI patients were revascularized using percutaneous coronary intervention and bypass surgery (628 [72.43%] and 87 [10.03%] respectively). During a mean follow-up of 7.69 ± 4.17 years, HF, recurrent ischemic events and SCA-VA occurred in 155 (17.9%), 245 (28.3%), and 40 (4.61%) patients respectively. Low ejection fraction (adjusted hazard ratio [HR] 0.95; 95% confidence interval [CI], 0.93-0.98; P < .001), intercurrent HF (adjusted HR 3.11; 95% CI, 1.39-6.95; P = .006) and recurrent ischemic events (adjusted HR 3.47; 95% CI, 1.68-7.18; P < .001) were associated with subsequent SCA-VA.ConclusionSCA-VA occurred in a small proportion of patients after MI and is associated with intercurrent HF and recurrent ischemic events.
| S-EPMC8276850 | biostudies-literature