Chronic Myocardial Infarction Research Articles

Podoplanin Positive Cell-derived Extracellular Vesicles Contribute to Cardiac Amyloidosis After Myocardial Infarction.

Amyloidosis is a major long-term complication of chronic disease; however, whether it represents one of the complications of post-myocardial infarction (MI) is yet to be fully understood. Using wild-type and knocked-out MI mouse models and characterizing in vitro the exosomal communication between bone marrow-derived macrophages and activated mesenchymal stromal cells (MSC) isolated after MI, we investigated the mechanism behind Serum Amyloid A 3 (SAA3) protein overproduction in injured hearts. Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage-derived SAA3 monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from a subset of activated MSC, which, in response to MI, acquire the expression of a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin (PDPN). Cardiac MSC PDPN+ communicate with and activate macrophages through their extracellular vesicles or exosomes. Specifically, MSC PDPN+ derived exosomes (MSC PDPN+ Exosomes) are enriched in SAA3 and exosomal SAA3 protein engages with Toll-like receptor 2 (TRL2) on macrophages, triggering an overproduction and impaired clearance of SAA3 proteins, resulting in aggregation of SAA3 monomers as rigid amyloid deposits in the extracellular space. The onset of amyloid fibers deposition alongside extra-cellular-matrix (ECM) proteins in the ischemic heart exacerbates the rigidity and stiffness of the scar, hindering the contractility of viable myocardium and overall impairing organ function. Using SAA3 and TLR2 deficient mouse models, we show that SAA3 delivered by MSC PDPN+ exosomes promotes post-MI amyloidosis. Inhibition of SAA3 aggregation via administration of a retro-inverso D-peptide, specifically designed to bind SAA3 monomers, prevents the deposition of SAA3 amyloid fibrils, positively modulates the scar formation, and improves heart function post-MI. Overall, our findings provide mechanistic insights into post-MI amyloidosis and suggest that SAA3 may be an attractive target for effective scar reversal after ischemic injury and a potential target in multiple diseases characterized by a similar pattern of inflammation and amyloid deposition. What is known? Accumulation of rigid amyloid structures in the left ventricular wall impairs ventricle contractility.After myocardial infarction cardiac Mesenchymal Stromal Cells (MSC) acquire Podoplanin (PDPN) to better interact with immune cells.Amyloid structures can accumulate in the heart after chronic inflammatory conditions. What information does this article contribute? Whether accumulation of cumbersome amyloid structures in the ischemic scar impairs left ventricle contractility, and scar reversal after myocardial infarction (MI) has never been investigated.The pathophysiological relevance of PDPN acquirement by MSC and the functional role of their secreted exosomes in the context of post-MI cardiac remodeling has not been investigated.Amyloid structures are present in the scar after ischemia and are composed of macrophage-derived Serum Amyloid A (SAA) 3 monomers, although mechanisms of SAA3 overproduction is not established. Here, we report that amyloidosis, a secondary phenomenon of an already preexisting and prolonged chronic inflammatory condition, occurs after MI and that amyloid structures are composed of macrophage-derived SAA3 monomers. Frequently studied cardiac amyloidosis are caused by aggregation of immunoglobulin light chains, transthyretin, fibrinogen, and apolipoprotein in a healthy heart as a consequence of systemic chronic inflammation leading to congestive heart failure with various types of arrhythmias and tissue stiffness. Although chronic MI is considered a systemic inflammatory condition, studies regarding the possible accumulation of amyloidogenic proteins after MI and the mechanisms involved in that process are yet to be reported. Here, we show that SAA3 overproduction in macrophages is triggered in a Toll-like Receptor 2 (TLR2)-p38MAP Kinase-dependent manner by exosomal communication from a subset of activated MSC, which, in response to MI, express a platelet aggregation-inducing type I transmembrane glycoprotein named Podoplanin. We provide the full mechanism of this phenomenon in murine models and confirm SAA3 amyloidosis in failing human heart samples. Moreover, we developed a retro-inverso D-peptide therapeutic approach, "DRI-R5S," specifically designed to bind SAA3 monomers and prevent post-MI aggregation and deposition of SAA3 amyloid fibrils without interfering with the innate immune response.

Novel Fibrillar and Non-Fibrillar Collagens Involved in Fibrotic Scar Formation after Myocardial Infarction.

Following myocardial infarction (MI), adverse remodeling depends on the proper formation of fibrotic scars, composed of type I and III collagen. Our objective was to pinpoint the participation of previously unreported collagens in post-infarction cardiac fibrosis. Gene (qRT-PCR) and protein (immunohistochemistry followed by morphometric analysis) expression of fibrillar (types II and XI) and non-fibrillar (types VIII and XII) collagens were determined in RNA-sequencing data from 92 mice undergoing myocardial ischemia; mice submitted to permanent (non-reperfused MI, n = 8) or transient (reperfused MI, n = 8) coronary occlusion; and eight autopsies from chronic MI patients. In the RNA-sequencing analysis of mice undergoing myocardial ischemia, increased transcriptomic expression of collagen types II, VIII, XI, and XII was reported within the first week, a tendency that persisted 21 days afterwards. In reperfused and non-reperfused experimental MI models, their gene expression was heightened 21 days post-MI induction and positively correlated with infarct size. In chronic MI patients, immunohistochemistry analysis demonstrated their presence in fibrotic scars. Functional analysis indicated that these subunits probably confer tensile strength and ensure the cohesion of interstitial components. Our data reveal that novel collagens are present in the infarcted myocardium. These data could lay the groundwork for unraveling post-MI fibrotic scar composition, which could ultimately influence patient survivorship.

Correlation between ventricular local impedance and tissue composition by MRI in chronic infarction

Abstract Background Local impedance (LI) mapping is feasible and provides additional tissue characterization of the ventricular tachycardia substrate. Data on tissue composition underlying different LI values are lacking. Purpose To correlate LI with tissue composition evaluated by magnetic resonance imaging (MRI) in a chronic myocardial infarction (MI) swine model. Methods One-month after a non-reperfused anterior MI, eighteen Landrace X Large White pigs underwent delayed-enhancement MRI (deMRI) and endocardial LI mapping. deMRI images were post-processed off-line with commercially available dedicated software; scar subtypes (with thresholds set at 40-60% of maximal pixel signal intensity [PSI]), border-zone corridors and left ventricular wall thickness were measured. LI thresholds were set using the blood-pool LI value to define low, intermediate, and high tissue resistance subtypes. LI maps were co-registered with deMRI for analyses. Results Low LI zones correlated with deMRI dense and transmural scar (exhibiting endo and epicardial PSI >60% in 91% and 80% of the cases, respectively). Intermediate LI tissue exhibited predominantly subendocardial scar with more heterogeneous composition (8%, 47% and 45% of the points had <40%, 40-60% and >60% endocardial PSI, respectively), and with less epicardial involvement (50% of points had epicardial PSI <40%). Border-zone corridors co-localized with intermediate LI tissue in most of the cases (77%). Low LI zones exhibited more pronounced wall thinning compared to intermediate LI tissue (p<0.001) (Figure 1). Conclusions LI correlated with scar density and transmurality on deMRI. Areas of low LI had higher proportion of dense, transmural scar and wall thinning compared to intermediate LI areas. MRI-detected border-zone corridors colocalized with intermediate LI in most cases.LI and deMRI data (endo and epi scar)LI and deMRI data (tissue thickness)

Tissue composition underlying local impedance in chronic infarction: an histological study

Abstract Background Local impedance (LI) mapping is feasible and provides additional tissue characterization of the ventricular tachycardia (VT) substrate. VT isthmuses are usually located in areas of intermediate LI while low LI regions did not actively participate in the VT circuit. Histological studies evaluating the tissue composition underlying different LI values are lacking. Purpose To describe the tissue composition underling different LI subtypes in a chronic myocardial infarction (MI) swine model. Methods One-month after a non-reperfused anterior MI, five Landrace X Large White pigs underwent endocardial LI mapping (figure 1). LI thresholds were set using the blood-pool LI value to define low, intermediate, and high tissue resistance subtypes. A navigated needle-catheter was used to inject methylene-blue at sites with intermediate and low LI to guide the ex vivo tissue localization. Tissue was obtained for further histological analysis. Low and intermediate LI zones were analysed. Results A total of six and eight samples were analysed for low and intermediate LI, respectively. Compared to low LI zones, intermediate LI tissue displayed less Collagen I (1.03±0.26 vs. 0.34±0.35%, p=0.0082), Collagen III (9.92±2.98 vs. 6.47±1.80%, p=0.0380) and Collagen Volume Fraction (10.92±2.77 vs. 6.81±1.92, p=0.0163), without differences in the overall fibrotic and adipocytic deposition (figure 2). No significant differences in the Cx43, CTnI and SERCA2 expression were observed. Conclusion LI subtypes showed distinctive histological composition. Intermediate LI sites displayed less collagen content (I, III and collagen volume fraction) compared to those with low LI.Endocardial LI mappingHystological analysis: Collagen Content

17 β-Estradiol ameliorates cardiac parasympathetic dysfunction following myocardial infarction in male mice

Background: Vagal dysfunction after chronic myocardial infarction (MI) is associated with an increased risk of ventricular tachycardia (VT)/ventricular fibrillation (VF) and increased mortality in heart failure. The incidence and outcomes of VT/VF are influenced by sex, with women having a lower incidence of VT/VF associated with ischemic heart disease. However, the mechanisms behind these sex differences remain unclear and could be due to sex differences in autonomic remodeling post-MI that is mediated by estrogen. Hypotheses: We hypothesized that estrogen improves vagal function after MI by reducing oxidative stress in vagal sensory neurons and improving vagal afferent/efferent reflexes and function. Methods: Mice with expression of channelrhodopsin (ChR2) in specific sensory afferent neurons were created by crossing vesicular glutamate transporter 2 (VGlut2)-IRES-Cre mice with ChR2-EYFP mice, and their offspring (Vglut2-ChR2-EYFP) used for optogenetic stimulation studies. Sham surgery (n=6) or MI (n=6) was performed in two separate groups of male mice. A third group of male mice (n=8) underwent 17β-Estradiol (E2) pellet (0.5 milligrams/pellet) implantation followed by MI (E2+MI) after 2.5 weeks. Terminal studies were performed 2-3 weeks post-MI/sham procedures by placing a blue light (473 nm) laser probe over the left cervical vagus in vivo to stimulate vagal sensory neurons (20 Hz, 10 & 20 msec stimulations for 5 sec). Heart rate (HR) and blood pressure (BP) responses were measured in response to optogenetic stimulation. Plasma E2 and nodose ganglion 4-hydroxynaneol (4HNE) levels, a marker of lipid peroxidation, were evaluated. Results: In response to optogenetic vagal stimulation, MI had reduced reflex heart rate responses vs. sham animals, while E2+MI mice demonstrated significantly better responses vs. MI and similar responses to sham animals (20 Hz, 10 msec: sham -59 ± 3%, MI -24 ± 3%, E2+MI -58 ± 4%, MI vs. E2+MI, P < 0.001; 20 Hz, 20 msec: sham -59 ± 4%, MI -31 ± 3%, E2+MI -60 ± 3%, MI vs. E2+MI, P < 0.001). In addition, while BP responses post-MI were reduced vs. sham, E2+MI male mice also demonstrated greater BP responses to optogenetic stimulation (20 Hz, 10 msec: sham -28 ± 4%, MI -12 ± 1%, E2+MI -27± 1%, MI vs. E2+MI, P < 0.001; 20 Hz, 20 msec: sham -32 ± 4%, MI -13 ± 1%, E2+MI -27 ± 5%, MI vs. E2+MI, P < 0.001). 4HNE levels were increased in MI vs. sham animals, while E2+MI mice demonstrated significant reductions in 4HNE levels (Sham 0.17 ± 0.09 μg/protein, MI 0.77 ± 0.11 μg/protein, E2±MI 0.26 ± 0.06 μg/protein, MI vs. E2+MI, P < 0.001). Finally, plasma measurements confirmed higher levels of estrogen in E2-implanted mice (MI 48 ± 10 pg/mL, E2+MI 850 ± 170 pg/mL, MI vs. E2+MI, P < 0.001). Conclusions: MI causes pathological vagal remodeling that is reflected in decreased sensory vagal neurotransmission and increased oxidative stress in the vagal ganglia. Parasympathetic dysfunction and oxidative stress are mitigated by estrogen, suggesting that estrogen may be an important factor in mitigating the resulting pathological autonomic remodeling post-MI that predisposes to VT/VF. NIHR01HL148190. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model.

The VICTORIA trial demonstrated a significant decrease in cardiovascular events through vericiguat therapy. This study aimed to assess the potential mechanisms responsible for the reduction of cardiovascular events with vericiguat therapy in a rabbit model of myocardial infarction (MI). A chronic MI rabbit model was created through coronary artery ligation. Following 4 weeks, the hearts were harvested and Langendorff perfused. Subsequently, electrophysiological examinations and dual voltage-calcium optical mapping studies were conducted at baseline and after administration of vericiguat at a dose of 5 μmol/L. Acute vericiguat therapy demonstrated a significant reduction in premature ventricular beat burden and effectively suppressed ventricular arrhythmic inducibility. The electrophysiological influences of vericiguat therapy included an increased ventricular effective refractory period, prolonged action potential duration, and accelerated intracellular calcium (Cai) homeostasis, leading to the suppression of action potential and Cai alternans. The pacing-induced ventricular arrhythmias exhibited a reentrant pattern, attributed to fixed or functional conduction block in the peri-infarct zone. Vericiguat therapy effectively mitigated the formation of cardiac alternans as well as the development of reentrant impulses, providing additional anti-arrhythmic benefits. In the MI rabbit model, vericiguat therapy demonstrates anti-ventricular arrhythmia effects. The vericiguat therapy reduces ventricular ectopic beats, inhibiting the initiation of ventricular arrhythmias. Furthermore, the therapy successfully suppresses cardiac alternans, preventing conduction block and, consequently, the formation of reentry circuits.

Association between Air Pollution Relating to Agricultural Residue Burning and Morbidity of Acute Cardiopulmonary Diseases in Upper Northern Thailand

In Northern Thailand, increasing seasonal agricultural residue burning has led to public concern about health risks. This study aimed to examine the associations between air pollutants related to agricultural residue burning and morbidity from acute cardiopulmonary diseases in upper Northern Thailand in 2018. An ecological study was conducted. Emergency room visits and hospitalizations for chronic obstructive pulmonary disease (COPD), stroke, myocardial infarction (MI), and asthma were extracted from the National Electronic Health Record database. We interpolated air pollution data to estimate weekly pollutant concentrations, including PM10, PM2.5, carbon monoxide, nitrogen dioxide, sulfur dioxide and ozone from 1 Jan to 31 Dec 2018. Associations between air pollution and health outcomes were analyzed using a mixed effect model incorporating different lag structures. Overall pollutant concentrations exceeded WHO air quality standard levels throughout March and April, which is the end of forest burning prohibition campaign. Morbidity from COPD, stroke, MI and asthma slightly increased over March–April. For every increase in PM2.5 level of 10 μg/m3, the relative risk of COPD, stroke, MI and asthma 1 week later was 1.10 (95% CI 1.09–1.12), 1.06 (1.05–1.08), 1.06 (1.04–1.08) and 1.06 (1.01–1.12), respectively. The effects of agricultural residue burning should be highlighted and policies should be developed to deter this practice.

Remnant Cholesterol, Not LDL Cholesterol, Explains Peripheral Artery Disease Risk Conferred by apoB: A Cohort Study.

Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction. apoB, remnant cholesterol, and LDL cholesterol were measured in 93 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25 347 of the individuals. Results were replicated in 302 167 individuals without statin use from the UK Biobank (2004-2010). In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings. PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.

Cardiac MRI assessment of myocardial viability in chronic myocardial infarction: how should we do it?

Cardiac MRI assessment of myocardial viability in chronic myocardial infarction: how should we do it?

Temporary extracorporeal life support: single-centre experience with a new concept.

The combination of veno-arterial extracorporeal membrane oxygenation with a micro-axial flow pump (ECMELLA) is increasingly used for cardiogenic shock (CS) therapy. We report our experience with a novel single-artery access ECMELLA setup with either femoral (2.0) or jugular venous cannulation (2.1), respectively. Data from 67 consecutive CS patients treated with ECMELLA 2.0 (n = 56) and 2.1 (n = 11) from December 2020 and December 2022 in a tertiary cardiac center were retrospectively analyzed. The mean age was 60.7 ± 11 years, 56 patients (84%) were male. CS aetiology was acute on chronic heart failure (n = 35, 52%), myocardial infarction (n = 13, 19.5%), postcardiotomy syndrome (n = 16, 24%) and myocarditis (n = 3, 4.5%). Preoperatively 31 patients (46%) were resuscitated, 53 (79%) were on a ventilator and 60 (90%) were on inotropic support. The median vasoactive inotropic score was 32, and the mean arterial lactate was 8.1 mmol/l. In 39 patients (58%), veno-arterial extracorporeal membrane oxygenation was explanted after a median ECMELLA support of 4 days. Myocardial recovery was achieved in 18 patients (27%), transition to a durable left ventricular assist device in 16 (24%). Thirty-three patients (n = 33; 49%) died on support (25 on ECMELLA and 8 on Impella after de-escalation), 9 (13%) of whom were palliated. Axillary access site bleeding occurred in 9 patients (13.5%), upper limb ischaemia requiring surgical revision in 3 (4.5%). Axillary site infection occurred in 6 cases (9%), and perioperative stroke in 10 (15%; 6 hemorrhagic, 4 thromboembolic). ECMELLA 2.0/2.1 is a feasible and effective therapy for severe CS. The single-artery cannulation technique is associated with a relatively low rate of access-related complications.

Donepezil attenuates progression of cardiovascular remodeling and improves prognosis in spontaneously hypertensive rats with chronic myocardial infarction.

The acetylcholinesterase inhibitor donepezil restores autonomic balance, reduces inflammation, and improves long-term survival in rats with chronic heart failure (CHF) following myocardial infarction (MI). As arterial hypertension is associated with a significant risk of cardiovascular death, we investigated the effectiveness of donepezil in treating CHF in spontaneously hypertensive rats (SHR). CHF was induced in SHR by inducing permanent MI. After 2 weeks, the surviving SHR were randomly assigned to sham-operated (SO), untreated (UT), or oral donepezil-treated (DT, 5 mg/kg/day) groups, and various vitals and parameters were monitored. After 7 weeks of treatment, heart rate and arterial hypertension reduced significantly in DT rats than in UT rats. Donepezil treatment improved 50-day survival (41% to 80%, P = 0.004); suppressed progression of cardiac hypertrophy, cardiac dysfunction (cardiac index: 133 ± 5 vs. 112 ± 5 ml/min/kg, P < 0.05; left ventricular end-diastolic pressure: 12 ± 3 vs. 22 ± 2 mmHg, P < 0.05; left ventricular +dp/dtmax: 5348 ± 338 vs. 4267 ± 114 mmHg/s, P < 0.05), systemic inflammation, and coronary artery remodeling (wall thickness: 26.3 ± 1.4 vs. 34.7 ± 0.7 μm, P < 0.01; media-to-lumen ratio: 3.70 ± 0.73 vs. 8.59 ± 0.84, P < 0.001); increased capillary density; and decreased plasma catecholamine, B-type natriuretic peptide, arginine vasopressin, and angiotensin II levels. Donepezil treatment attenuated cardiac and coronary artery remodeling, mitigated cardiac dysfunction, and significantly improved the prognosis of SHR with CHF.

Prevalence of complete edentulism among US adults 65 years and older: A Behavioral Risk Factor Surveillance System study from 2012 through 2020

BackgroundThe rapid growth of the older adult population in the United States and their increased risk of edentulism make it essential to analyze trends and factors associated with edentulism. MethodsData were obtained from the Behavioral Risk Factor Surveillance System from 2012 through 2020. US- and state-level trend lines were reported. Multiple logistic regression analyses were used to evaluate the association between self-reported complete edentulism and demographic characteristics, chronic diseases, smoking status, and health insurance status. Multiple imputations were used to address the missing data. ResultsA total of 771,513 (weighted n = 50,410,576) participants were included in the study. There was a significant (P = .021) downward trend in the prevalence of edentulism from 2012 (16.36%) through 2020 (13.54%). Having less than a high school education, being a smoker, being non-Hispanic Black, having an annual household income less than $75,000, and having chronic conditions, including diabetes, myocardial infarction, arthritis, depression, and stroke, were significantly associated with complete edentulism. ConclusionsDespite a decrease in prevalence of edentulism, disparities based on race, income, and education still exist. Edentulism is associated with chronic diseases in older adults. Practical ImplicationsPublic health initiatives should be aimed at reducing the impact of edentulism and improving overall quality of life among older adults. Community health programs allocating resources to improve access to affordable care, reducing precursors to edentulism, expanding dental coverage, and promoting oral and general health awareness are vital components of these efforts.

Automated assessment of cardiac pathologies on cardiac MRI using T1-mapping and late gadolinium phase sensitive inversion recovery sequences with deep learning

BackgroundA deep learning (DL) model that automatically detects cardiac pathologies on cardiac MRI may help streamline the diagnostic workflow. To develop a DL model to detect cardiac pathologies on cardiac MRI T1-mapping and late gadolinium phase sensitive inversion recovery (PSIR) sequences were used.MethodsSubjects in this study were either diagnosed with cardiac pathology (n = 137) including acute and chronic myocardial infarction, myocarditis, dilated cardiomyopathy, and hypertrophic cardiomyopathy or classified as normal (n = 63). Cardiac MR imaging included T1-mapping and PSIR sequences. Subjects were split 65/15/20% for training, validation, and hold-out testing. The DL models were based on an ImageNet pretrained DenseNet-161 and implemented using PyTorch and fastai. Data augmentation with random rotation and mixup was applied. Categorical cross entropy was used as the loss function with a cyclic learning rate (1e-3). DL models for both sequences were developed separately using similar training parameters. The final model was chosen based on its performance on the validation set. Gradient-weighted class activation maps (Grad-CAMs) visualized the decision-making process of the DL model.ResultsThe DL model achieved a sensitivity, specificity, and accuracy of 100%, 38%, and 88% on PSIR images and 78%, 54%, and 70% on T1-mapping images. Grad-CAMs demonstrated that the DL model focused its attention on myocardium and cardiac pathology when evaluating MR images.ConclusionsThe developed DL models were able to reliably detect cardiac pathologies on cardiac MR images. The diagnostic performance of T1 mapping alone is particularly of note since it does not require a contrast agent and can be acquired quickly.

Mechanism of Ventricular Tachycardia Occurring in Chronic Myocardial Infarction Scar.

Cardiac arrest is the leading cause of death in the more economically developed countries. Ventricular tachycardia associated with myocardial infarct is a prominent cause of cardiac arrest. Ventricular arrhythmias occur in 3 phases of infarction: during the ischemic event, during the healing phase, and after the scar matures. Mechanisms of arrhythmias in these phases are distinct. This review focuses on arrhythmia mechanisms for ventricular tachycardia in mature myocardial scar. Available data have shown that postinfarct ventricular tachycardia is a reentrant arrhythmia occurring in circuits found in the surviving myocardial strands that traverse the scar. Electrical conduction follows a zigzag course through that area. Conduction velocity is impaired by decreased gap junction density and impaired myocyte excitability. Enhanced sympathetic tone decreases action potential duration and increases sarcoplasmic reticular calcium leak and triggered activity. These elements of the ventricular tachycardia mechanism are found diffusely throughout scar. A distinct myocyte repolarization pattern is unique to the ventricular tachycardia circuit, setting up conditions for classical reentry. Our understanding of ventricular tachycardia mechanisms continues to evolve as new data become available. The ultimate use of this information would be the development of novel diagnostics and therapeutics to reliably identify at-risk patients and prevent their ventricular arrhythmias.

Piezo1-Mediated Neurogenic Inflammatory Cascade Exacerbates Ventricular Remodeling After Myocardial Infarction.

Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel-mediated neurogenic inflammatory cascade underlies ventricular remodeling-related mechanotransduction. By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)-specific Piezo1 knockdown rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling. Subsequently, neutralizing antibody-mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro. Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron-specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron-specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI. Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction.

Long-term toxicities after allogeneic hematopoietic stem cell transplantation with or without total body irradiation: a population-based study in Korea.

To compare long-term toxicity incidences, including secondary cancer (SC) with or without total body irradiation (TBI), in Asian patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) using a nationwide database. We identified 4,554 patients receiving HSCT for leukemic disease from 2009 to 2016 using the healthcare bigdata system of Korea. Incidence rate ratios (IRRs) for SC, cataracts, hypothyroidism, chronic kidney disease (CKD), myocardial infarction, or strokes were compared, and standardized incidence ratios (SIR) of SC was also estimated. TBI was conducted on 1,409 patients (30.9%). No overall survival differences based on TBI were observed. With a median follow-up duration of 58.2 months, 143 patients were diagnosed with subsequent SC (3.4%). Incidence rates per 1,000 person-year were 6.56 (95% confidence interval [CI], 4.8-8.8) and 7.23 (95% CI, 5.9-8.8) in the TBI and no-TBI groups, respectively (p = 0.594). Also, the SIR (95% CI) was not significantly increased by TBI (1.32 [0.86-1.94] vs. 1.39 [1.08-1.77] in the no-TBI group). In the young age group (0-19 years), SIRs were increased in both groups regardless of TBI (8.60 vs. 11.96). The IRRs of cataracts (1.60; 95% CI, 1.3-2.0), CKD (1.85; 95% CI, 1.3-2.6), and hypothyroidism (1.50; 95% CI, 1.1-2.1) were significantly increased after TBI. However, there were no significant differences in the occurrence of myocardial infarction and stroke according to TBI. Our results suggest that modern TBI may not additionally increase the risk of SC after allogeneic HSCT, although increased risks of other diseases were noted. Physicians should carefully consider individualized risks and benefits of TBI, with a particular focus by age group.

Decreased Heart Rate After Dapagliflozin Treatment In Gottingen Minipigs With Chronic Myocardial Infarction

Decreased Heart Rate After Dapagliflozin Treatment In Gottingen Minipigs With Chronic Myocardial Infarction

Kiosk 6R-FB-06 - Capturing Acute and Chronic Myocardial Infarct by Rotating FBame Relaxation Times in Mice

Kiosk 6R-FB-06 - Capturing Acute and Chronic Myocardial Infarct by Rotating FBame Relaxation Times in Mice

Simultaneous Viability Assessment and Invasive Coronary Angiography Using a Therapeutic CT System in Chronic Myocardial Infarction Patients.

In a preclinical study using a swine myocardial infarction (MI) model, a delayed enhancement (DE)-multi-detector computed tomography (MDCT) scan was performed using a hybrid system alongside diagnostic invasive coronary angiography (ICA) without the additional use of a contrast agent, and demonstrated an excellent correlation in the infarct area compared with histopathologic specimens. In the present investigation, we evaluated the feasibility and diagnostic accuracy of a myocardial viability assessment by DE-MDCT using a hybrid system comprising ICA and MDCT alongside diagnostic ICA without the additional use of a contrast agent. We prospectively enrolled 13 patients (median age: 67 years) with a previous MI (>6 months) scheduled to undergo ICA. All patients underwent cardiac magnetic resonance (CMR) imaging before diagnostic ICA. MDCT viability scans were performed concurrently with diagnostic ICA without the use of additional contrast. The total myocardial scar volume per patient and average transmurality per myocardial segment measured by DE-MDCT were compared with those from DE-CMR. The DE volume measured by MDCT showed an excellent correlation with the volume measured by CMR (r=0.986, p<0.0001). The transmurality per segment by MDCT was well-correlated with CMR (r=0.900, p<0.0001); the diagnostic performance of MDCT in differentiating non-viable from viable myocardium using a 50% transmurality criterion was good with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 87.5%, 99.5%, 87.5%, 99.5%, and 99.1%, respectively. The feasibility of the DE-MDCT viability assessment acquired simultaneously with conventional ICA was proven in patients with chronic MI using DE-CMR as the reference standard.

MRI Accurately Visualizes RF Ablation Delivery Targeted to MRI-Defined Arrhythmia Substrates in the Left Ventricle.

Investigate the capacity of MRI to evaluate efficacy of radiofrequency (RF) ablations delivered to MRI-defined arrhythmogenic substrates. Baseline MRI was performed at 3T including 3D LGE in a swine model of chronic myocardial infarct (N=8). MRI-derived maps of scar and heterogeneous tissue channels (HTCs) were generated using ADAS 3D. Animals underwent electroanatomic mapping and ablation of the left ventricle in CARTO3, guided by MRI-derived scar maps. Post-ablation MRI (in vivo at 3T in 5/8 animals; ex vivo at 1.5T in 3/8) included 3D native T1-weighted IR-SPGR (TI=700-800ms) to visualize RF lesions. T1-derived RF lesions were compared against excised tissue. The locations of T1-derived RF lesions were compared against CARTO ablation tags, and segment-wise sensitivity and specificity of lesion detection were calculated within the AHA 17-segment model. RF lesions were clearly visualized in HTCs, scar, and myocardium. Ablation patterns delivered in CARTO matched T1-derived RF lesion patterns with high sensitivity (88.9%) and specificity (94.7%), and were closely matched in registered MR-EP data sets, with a displacement of 5.4 ±3.8mm (N=152 ablation tags). Integrating MRI into ablative procedures for RF lesion assessment is feasible. Patterns of RF lesions created using a standard 3D EAM system are accurately reflected by MRI visualization in healthy myocardium, scar, and HTCs comprising the MRI-defined arrhythmia substrate. MRI visualization of RF lesions can provide near-immediate (<24h) assessment of ablation, potentially indicating whether critical MRI-defined ventricular tachycardia substrates have been adequately ablated.