Increased afterload following myocardial infarction promotes conduction-dependent arrhythmias that are unmasked by hypokalemia.
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ABSTRACT:
SUBMITTER: Motloch LJ
PROVIDER: S-EPMC5547890 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction. Recently, a novel mechanism for oxidative CaMKII activation was discovered in the heart. Here, we provide the first report of CaMKII oxidation state in a well-validated, large-animal model of heart disease. Specifically, we observe increased levels of oxidized CaMKII in the infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for CaMKII in common cardiovascular disease. To study the role of oxidation-dependent CaMKII activation in creating a pro-arrhythmia substrate following myocardial infarction, we developed a new mathematical model of CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced CaMKII activity in the infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for CaMKII activation in the infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.
| S-EPMC2778128 | biostudies-literature
Project description:RationaleNerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated.ObjectiveTo define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI).Methods and resultsImmunostaining for NGF and TrkA was performed on heart samples from humans deceased of MI or unrelated pathologies. To study the post-MI functions of endogenous NGF, a NGF-neutralizing antibody (Ab-NGF) or nonimmune IgG (control) was given to MI mice. To investigate the NGF therapeutic potential, human NGF gene or control (empty vector) was delivered to the murine periinfarct myocardium. Results indicate that NGF is present in the infarcted human heart. Both cardiomyocytes and endothelial cells (ECs) possess TrkA, which suggests NGF cardiovascular actions in humans. In MI mice, Ab-NGF abrogated native reparative angiogenesis, increased EC and cardiomyocyte apoptosis and worsened cardiac function. Conversely, NGF gene transfer ameliorated EC and cardiomyocyte survival, promoted neovascularization and improved myocardial blood flow and cardiac function. The prosurvival/proangiogenic Akt/Foxo pathway mediated the therapeutic benefits of NGF transfer. Moreover, NGF overexpression increased stem cell factor (the c-kit receptor ligand) expression, which translated in higher myocardial abundance of c-kit(pos) progenitor cells in NGF-engineered hearts.ConclusionsNGF elicits pleiotropic beneficial actions in the post-MI heart. NGF should be considered as a candidate for therapeutic cardiac regeneration.
| S-EPMC2881000 | biostudies-literature
Project description:Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (?30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.
| S-EPMC4599491 | 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
Project description:The mechanism mediating the development of ventricular arrhythmia (VA) after acute myocardial infarction (AMI) is still uncertain. Thrombin receptor (TR) activation has been proven to be arrhythmogenic in many other situations, and we hypothesize that it may participate in the genesis of post-AMI VA. Using a left coronary artery ligation rat model of AMI, we found that a local injection of hirudin into the left ventricle (LV) significantly reduced the ratio of VA durations to infarction sizing, whereas injection of thrombin receptor-activating peptide (TRAP) increased the ratios of VA duration to infarction sizing. The effects of TR activation on whole-cell currents were investigated in isolated myocytes. TRAP increased a glibenclamide-sensitive outward current. Pretreatment of rats with glibenclamide (4 mg/kg intraperitoneally) eliminated the effects of a local injection of TRAP on the ratios of VA durations to infarction sizing. TR mRNA and protein expression in the ischemic left ventricle had reached its peak by 20 min postligation in the rat AMI model (P < 0.05). TR-immunoreactive myocytes were observed in infarcted LV but were seldom seen in the right ventricle or in the normal heart. By 60 min, TR transcript levels had returned to control levels. We conclude that increased TR activation and expression in the infarcted LV after AMI may contribute to VA through a mechanism involving glibenclamide-sensitive potassium channels.
| S-EPMC2213895 | biostudies-literature
Project description:BackgroundAn association between testosterone therapy (TT) and cardiovascular disease has been reported and TT use is increasing rapidly.MethodsWe conducted a cohort study of the risk of acute non-fatal myocardial infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. We compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). We also compared post/pre rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors (PDE5I; sildenafil or tadalafil, N = 167,279), and compared TT prescription post/pre rates with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation.ResultsIn all subjects, the post/pre-prescription rate ratio (RR) for TT prescription was 1.36 (1.03, 1.81). In men aged 65 years and older, the RR was 2.19 (1.27, 3.77) for TT prescription and 1.15 (0.83, 1.59) for PDE5I, and the ratio of the rate ratios (RRR) for TT prescription relative to PDE5I was 1.90 (1.04, 3.49). The RR for TT prescription increased with age from 0.95 (0.54, 1.67) for men under age 55 years to 3.43 (1.54, 7.56) for those aged ≥ 75 years (p trend = 0.03), while no trend was seen for PDE5I (p trend = 0.18). In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90 (1.49, 5.62) for TT prescription and 1.40 (0.91, 2.14) for PDE5I, and a RRR of 2.07 (1.05, 4.11).DiscussionIn older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased.
| S-EPMC3905977 | biostudies-literature
Project description:Infiltration by dendritic cells (DCs) is markedly increased in the infarcted area following myocardial infarction (MI), and DC ablation has been shown to impair angiogenesis in mice post?MI. Exosomes (EXs) have long been known to act as messengers between cells; however, whether EXs derived from DCs can enhance myocardial angiogenesis post?MI remains unknown. The aim of the present study was to elucidate whether EXs derived from DCs induce myocardial angiogenesis via paracrine signaling post?MI. In vitro, suspensions of mouse bone marrow?derived DCs (BMDCs) were incubated with the supernatant of necrotic or normal cultured HL?1 myocardial cells (as the MI or control group, respectively) for 24 h. EXs isolated from the supernatant of BMDCs were termed DEXs, which were added to primary cultures of rat cardiac microvascular endothelial cells (CMECs), and angiogenesis was evaluated by measuring tube formation and vascular endothelial growth factor (VEGF) expression. In vivo, different groups of DEXs were injected into the infarcted myocardium of MI model mice. Then, angiogenesis was evaluated by measuring the number of vessels and the expression of VEGF and CD31 in the infarcted myocardium using immunohistochemistry. Moreover, the expression profile of microRNAs (miRNAs or miRs) in splenic DCs of MI model mice was analyzed by Affymetrix miRNA 4.0 chip assays, then certified in DEXs by reverse transcription?quantitative PCR analysis. Finally, miRNA?loaded DEXs were used to induce tube formation by CMECs and angiogenesis in MI model mice. It was observed that, compared with the control group, DEXs from the MI group significantly upregulated the expression of VEGF in CMECs, enhanced tube formation by CMECs, and upregulated the expression of VEGF and CD31 in the infarcted myocardium of MI model mice. miR?494?3p and miR?16a?5p, which are associated with angiogenesis, were significantly upregulated in splenic DCs of MI model mice by Affymetrix miRNA 4.0 chip assays, miR?494?3p was significantly upregulated and highly enriched in DEXs from the MI group compared with the control, and DEX?miR?494?3p enhanced tube formation by CMECs and angiogenesis in mice post?MI. These results suggest that miR?494?3p may be secreted from DCs via EXs and promotes angiogenesis post?MI. These findings indicate a novel DEX?based approach to the treatment of MI.
| S-EPMC7723512 | biostudies-literature
Project description:There are limited data on arrhythmias in acute myocardial infarction with cardiogenic shock (AMI-CS). Using a 17-year AMI-CS population from the National Inpatient Sample, we identified common arrhythmias - atrial fibrillation (AF), atrial flutter, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, and atrioventricular blocks (AVB). Admissions with concomitant cardiac surgery were excluded. Outcomes of interest included temporal trends, predictors, in-hospital mortality, and resource utilization in cohorts with and without arrhythmias. Of the 420,319 admissions with AMI-CS during 2000 to 2016, arrhythmias were noted in 213,718 (51%). AF (45%), ventricular tachycardia (35%) and ventricular fibrillation (30%) were the most common arrhythmias. Compared with those without, the cohort w`ith arrhythmias was more often male, of white race, with ST-segment elevation AMI-CS presentation, and had higher rates of cardiac arrest and acute organ failure (all p <0.001). Temporal trends of prevalence revealed a stable trend of atrial and ventricular arrhythmias and declining trend in AVB. The cohort with arrhythmias had higher unadjusted (42% vs 41%; odds ratio [OR] 1.03 [95% confidence interval 1.02 to 1.05]; p <0.001), but not adjusted (OR 1.01 [95% CI 0.99 to 1.03]; p = 0.22) in-hospital mortality compared with those without. The cohort with arrhythmias had longer hospital stay (9 ± 10 vs 7 ± 9 days; p <0.001) and higher hospitalization costs ($124,000 ± 146,000 vs $91,000 ± 115,000; p <0.001). In the cohort with arrhythmias, older age, female sex, non-white race, higher co-morbidity, presence of acute organ failure, and cardiac arrest, predicted higher in-hospital mortality. In conclusion, cardiac arrhythmias in AMI-CS are a marker of higher illness severity and are associated with greater resource utilization.
| S-EPMC7261623 | biostudies-literature
Project description:Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome--apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.
| S-EPMC3241791 | biostudies-literature